(logo whooshing) (upbeat bright music) - So I'm gonna mix a little
bit of the discussion of the immune system,
notably the immune system that you probably don't know about. Many of you know about the immune system as the thing that protects you
against pathogens and viruses and when you get a shot
in the arm, a vaccination, you're essentially, we all understand that you're teaching your immune system about something that's
foreign and dangerous so that you can respond to it later For example, the flu virus or
flu vaccine or measles vaccine or any of the things you had as children. And what's unique about the immune system, obviously it remembers. So you know you got a
vaccine when you were a kid and many of you are still protected by that vaccine right now. So we all understand that
about the immune system, but I want to try to
teach you a little bit about some of the hidden
unknowns about the immune system and the things its doing and disease, but I will focus a lot on the cancer story because it's an illustrate
of what we can do using the immune system and
what we now understand of it. So I'm gonna do that a
little bit through the lens of how my lab studies the biology. So I have a little bit of science, real science-centric talk
and then try to get into the basic fundamentals. I'm assuming that'll hit
everybody just about right. So my view of the immune system starts by studying how things
take place in real time. And so it's a Yogi Berra quote that says, "It's amazing how much you can understand "by just watching something." And so we watch things at a
level of individual molecules. This is a density diagram
of an immunoglobulin, this is a molecule on the
surface of the immune cell. And I'm gonna tell you a
little bit about how image through microscopy, individual cells. We're gonna learn about
these cells called T cells that are the red or the green guys here interacting with some of their
partners here in the red. And I'll show you a movie
of that in just a moment. My lab also looks into arrays of cell. So this is a developing breast carcinoma, this is a ball of tumor
cells in black here that you're not seeing, but all the red, those are the green, the
yellow, and red, and blue cells around that are your immune system. So your immune system
is really omnipresent. It's in all of your tissue right now serving you, getting to know you, it's kind of like another
brain that you have. And ultimately you know the
way that I tend to view things is that small things give rise to certainly larger things. Including small cells then
get together to make tissues. And the tissues at some
point and how they function, determine very important things like whether you live or die. So this is the response
in melanoma patients to a drug that we made over
at Berkeley some years ago and you can see people
that are living out now to 15, 20 plus years that are cured and then the second round of those drugs with about 50% of the people that, sorry, should have mentioned
that in this particular drug, that a patient population
normally dies within six months, so you know you're seeing about
half the people are cured. So that's a really big
change from about five or 10 years ago. And it's in large part
due to our understanding of the immune system, so that's good. So I'm gonna show you this movie. It's a little bit of a
rendering of an interaction of two immune cells
because it demonstrates something I think is
really important biology, you know the biology level is the concept that your body works
because all your cells are agreeing with each other. They're coming together purposely and to tell each other information and really your immune
system is about information. It's saying this thing is
foreign, this thing is myself, and we'll talk a little
bit about the is idea about who everyone in this
room is ideologically. You are a collection of the cells of your, that were derived from your
parents as a single egg that has now become quite diverse. Both in terms of their function, but each one is also mutuganized under the influence of
the sunlight, for example. And so your body is quite a mix of, your identity is quite diverse. And then of course you
have the microbiomes too. You're all colonized with bacteria that you'll probably think
we'll learn in the lecture. So if you watch this movie, so this is a very high
resolution image that we take where the T cell here, you
know normally if you look in a normal light microscope, would be kind of a round ball. And you'll see things in magazine articles where it seems like that. But if you watch this movie, you'll see that this T cell
has a lot of these little, I call 'em microvilli, or
finger-like projections and they probe the world
and they're actually looking to find stuff. It's like when the doctor
palpates your stomach trying to feel things. Essentially T cells will do that. The other cell on the
other hand is actually gonna meet it halfway, so this rotates just to give you a sense of this contact. There's a round T cell
or more or less round with these little projections and you can see how these
are kind of palpating the world at large. Right now you can't see this interface, but we're gonna break it away for you here because we collected
the data in such a way that you can show that. And you can see how these
little fingers are pointing out to try to find stuff. But meanwhile, this cell
has extended itself down to be seen. I'm not sure if you caught that, but essentially the
cells are complimentary. It's not that one cell is a flat surface and the other one is probing it. Both cells have kind of made
this attempt to communicate. They've really made this
sort of attempt to handshake and that's a really important
feature of the immune system as it's trying to convey information about what all it's seen
in various different ways. So primarily tonight, I
wanted to focus on this idea of how many, many cells working together create the biology that is
really health and disease and we been focusing on the Immune System. And I'm gonna do that, as I
said in the context of cancer. So many of you understand,
I think, the idea of cancer. Fundamentally it's shown
here within a tissue, a collection of these very
red, angry, bad cells, which are cells that have gone rogue. Normally all the cells in your body have some sort of rules
about when they can divide and when they can repopulate. Maybe you need to repair
if you scratch your skin or something, but what happens in cancer is you get cells that don't
obey the rules anymore, right? So they become a little bit
more like a free colony. And in the past we thought,
okay well let's target that. And so until about 10 years ago, most all the drug industry,
all the sort of intuition said let's just figure out how these cells are doing that and let's
target that pathway. Let's target that feature of them. Maybe they've lost control
because of a particular gene that they've turned on or the gene that they've turned off. So let's make a drug against that. But what that lacked
in insight was the idea that tumors are mutating. The reason they got to be this way is because they've changed themselves and they're constantly
in a state of change. And so if you drug one aspect of them, they'll just change that right? So that's been the
experience of chemo therapies and that's why you hear
about people going back into remission and having a
recurrence of their cancer. At some point the cancer gets smarter, it gets lucky and it
mutates so that the drugs no longer works and then of
course you're in trouble again. But if you look at the tumor as a whole, there is in fact the red
cells that we think of as these angry cells that
are doing all the things that I've just mentioned. But always, and we always recognized this but we didn't really understand it, they're always surrounded
by a group of cells that are actually immune cells. They're cells of your
white blood cell system that you're thinking,
you have blood drawn, these little green cells here are a kind of white blood cells called T cells and these
kind of star-shaped cells I'll tell you about a little bit later are cells that are called
macrophages and dendritic cells. And even now, as I'll
show you in some movies, your body is being patrolled
by these cells all the time. So all tissue has some of these around it, but tumors have quite a few. So tumors actually
recruit the immune system to provide them with protection. I'm gonna show you a little bit of movie that we take in the lab and this is actually
a mouse mammary tumor. This is equivalent of what's called luminal B breast cancer in humans. The black space, again we're not actually highlighting the tumor at all. What I've got highlighted
are two kinds of immune cells in green and yellow and then the purple is actually blood flow
flowing around these. So normally a duct in
mammary, you know flow, they branch and they produce milk to give to children. But in the case of cancer,
those ducts fill up with balls of tumor
cells and then they avert and actually break up. This is the point where you
have balls of tumor cells within the ducts. And so many mini ones are filling in and we need a response here. And so as you watch this
movie, I think this is sped up, this is the actual real
time is shown down here. So you know roughly a hundred
fold, faster than normal. But I think you get the
sense that this is really a EV active community. Again the tumor is all the black. We're looking only here
at the immune system that is part of the
tumor micro environment. The environment that surrounds the tumor and gives it life. And again, we'll come into
what some of these cells are as I play this movie for
you a couple of other times and a few others to take the dream home, but at this point I just
want you to recognize the idea that there is an
immune system in the green. And the green cells and yellow cells are two different cell types and that they have different functions and different activities
and just maybe absorb that. Okay, so what are they? So I'm gonna give you
about four or five slides to introduce you to the players of this and maybe some of you will have seen this when you go to the doctor and you have a whole blood cell count. But some cell types
that I want to give you some names to, so we named the tumor as I showed you here, it's red. There were the black spaces in those movies that I showed you. The cell here, this is a
short hand for macrophage. Macro mean big in Greek
and then phage, eater, so this is a big eater. We also call 'em sometimes
phagocytes, cells that eat. We'll talk about two kinds
of what I call lymphocytes, B cells and T cells. And T cells come in various flavors and we give them names and some of them are a little bit more confusing. But these are CD8 T cells,
cytotoxic T lymphocytes, so you have all the very, we like to confuse people,
but ultimately these are all called lymphocytes. And then similar to macrophages, there's variations of T
cells that are macrophages call for example, dendritic cells. And then most tumors are also
surrounded by some element of the tissue that they
originally came from. You know they're breaking out of it so we often refer that just as stroma. So this purple border that I drawing here will maybe might have
been the original barrier of the ducts for example. And then the tumor growing within there. So that gives you a little introduction, but I'm gonna go into
two particular component cell types that I need you to understand to sort of see how the
immune system works. And this comes to the fundamental question I asked in here earlier, who are you? What is yourself and who
are you defending against when you're thinking
about your world at heart? And I want you to maybe
change that a little bit through the course of the night where you say, maybe a little bit, this is gonna be political,
sorry I'll say this, but you know a little anti-Trump here, just say that we are a
community that accepts immigrants into our world
and we make peace with them and that's actually how
societies are generally, you know they generally function. The immune system actually
has more of a roll to do that than to defend you against things. In other words, it's much
safer and it's much easier to be at harmony with the world outside, the bacteria that are on
your skin or in your gut, than it is to be constantly
fighting with them. Because if you're fighting
with them all the time, you're in a constant state of inflammation and you have a tendency
to damage yourself. And so there's a lot of
disease the immune system associated with over zealous response to the world outside you. And the world outside
really is the world on you. You have a lot of bacteria on your skin, you know a lot of bacteria in your guts. Gut for example, about 10 times
more bacteria in your body than you have cells of your own. All right, so there's a real
need for the immune system at some point to just okay,
this is a super organism. The self is a little bit of
a mixture between the cells that I started out with,
the cells that I've become through aging and the food
I eat, and the bacteria that are on my body. But this brings up the
question of how do you know. How do you know foreign from self? How do you know that something on you is a bad bacteria versus a good bacteria? Okay, so there's a cell type, there's two cell types
that do that for you. And the first one's, you'll recognize some of the parts of these
from things you've heard and probably in the
clinic or what have you. The first ones are called B cells. And B cells have the feature
that on their surface, each one has a unique little
sort of catcher's mitt that can catch things
from the world at large. And you have on the order
of like 10 to the ninth different B cells in your body. And they each have a little
different catcher's mitt for catching different
things in the environment. So they literally can just
kind of detect the universe at different things that are in the wild. And they can see for
example, like a bacteria, and when they see a
bacteria, they make sure to become what's called a plasma cell, that is basically a form of them that makes tons and tons of secreted forms of the very same receptor
that was on their surface in the first place, that
special catcher's mitt. And it then goes to your blood and these are called antibodies. And so if you ever get vaccinated, the idea of most
vaccinations is you bring in like a little bit of viral
particles from the shot you get and your body then learns,
okay that's something bad and these plasma cell
reactions that I'm showing you take place and your body
makes a ton of antibodies against those things. And then the next time the
viral particle comes in, it gets sopped up. It's literally coated
with all the antibodies that are in your blood. And many of you maybe also would have had something if you've been
in a foreign country called passive vaccination
where you get like horse serum. Literally horses were given the thing that you're trying to
be vaccinated against and you can be given these
antibodies as an injection. Since usually you're used to getting like five milliliters of
horse serum in your butt and it was really painful,
but you know it protected you while you were in Asia and
you didn't have to have this reaction to go on and you could be immediately protected. So this is a form of recognition right? So each of these is very unique. One of these might
recognize A form of flu, but another B cell in
your body may recognize a different form of flu. So when you go in to take a flu shot, you're educating some of
these to become flu reactive to make a whole bunch of antibodies so that your blood is just
full of these collections of antibodies that are
against different things and that provides you protection, right. There's another set of cells
that are equally important, perhaps even more important, particularly in the concept of viruses. And so these are called B cells. It has a very weird origin. They're found originally
in the bursa of Fabricius which is the little part
of the bone of birds. And so they were first found there and so they were called B cells, like bursa of Fabricius
is a little region. T cells are in contrast by name because they come through a little organ that's just above your
heart called the thymus. And the thymus is most
famous if you're culinary, it's one of the sweet breads, (chuckles) if you eat French food. So the thymus and the pancreas
are these very rich organs that you can, or if you go to
South America and Argentina, they'll put them on a
parilla, they're delicious. Anyway, but they serve a
very important function because both of those are places where these immune cells are developing. All right so the bursa
is where you make B cells and it's actually the
bone marrow in humans is where ewe make our B cells. So you can think of
bone marrow if you want. And T cells come through the thymus. And so what T cells do that are different, is that T cells also have
a receptor on their surface and here it's just showing
the surface of a T cell would also be what, I
showed you one, right? But imagine there's a sphere for one. It has a T cell receptor on its surface and what it recognizes is a
little protein that is part, is on every one of the rest of your cells that is a little carrier protein. It's called major
histocompatibility complex or MHC and it carries a peptide. It carries a little bit
of anything in the world. And this can be, a peptide
is piece of a protein right? And so you can have pieces
of protein from viruses, you can have pieces of
proteins that are of yourself, you can have pieces of protein
that come from bacteria, and all of them get put
into a little groove. This molecule has a little groove in it and the base of this molecule displays peptides to
this T cell and says hey, here's something I saw. This cell type can eat
material and then it might put it on surface of one of these things and then the T cells sees that and it's kind of a dual recognition. The T cell has to both see these molecule and it also has to see this peptide. And the reactions that
sort of become important is that these things have
relationship to each other. So we'll learn more about phagocytes. So if a phagocytes eats a bacteria, it can put pieces of that
bacteria and peptides on its surface to present to T cells. It can also, the T cell can
then interact with the B cell that is also seeing the same bacteria and so they can have a
little conjugate reaction, like one of the ones I showed
you in the earlier movies. And the net result of
this is maybe the B cells make a ton of themselves
and they make antibodies and the T cells make copies of themselves, ready to see them wherever
that peptide may show up again. And so the immune system
is really like this memory. It has this memory of all
the things that have happened and there's two kinds of
cells that really see that in the form of the molecular structure of everything else around you. These little peptides in one case or the whole thing in the
case of B cells right? You got these kind of specialized cells that see things very specifically. So to give this a little bit of flavor, like you can see this anatomically, I have to describe something
called lymph nodes. And many of you will know
these most intimately through your mother feeling your glands. The glands right here,
people remember this right? So if you have a cold,
what your mother or you are feeling or your doctor
is actually your lymph nodes. So you have a series of lymph
nodes all over your body that are kind of like, if
you want to think of this as an army analogy, your
immune system raids itself and the lymph nodes is
kind of like a base. And that's the place
where the immune system kind of has its home. And there's different zones. These are basically sacs
of cells, of immune cells. And there are some zones
that have B cells in them. You know this is basically, this is, sort of to give you a dimensionality, this is not very well to scale. This can hold around
10 million total cells in each of your lymph nodes, maybe more depending on which one it is. And when you get a cold or a flu, the reason why your glands swell is because you're getting
an amazing immune response. And that's how your mother or you know that you're having a
response to like a flu or a local cold, is that
those lymph nodes expand as the immune system expands
learning about the pathogen or the foreign thing and
then starting to make copies of itself in order to handle it. And I'll show you a little bit of movies in real time how that works, but again, keep in mind that this is zonal. There's different regions
of this that we can look at. And the way we do this in
the lab to give you a flavor, we either can use bio Ts
coming form the clinic or more often we do this in mouse models because of the accessibility
of studying things and they're really reliable, et cetera. So we can put for example, labeled T cells from one
mouse into another mouse and we might do some sort
of vaccination for example and then we can either
put that into literally, convert that mouse
underneath the microscope or we could take an organ from it in order to study the
cells within the organ and understand how
they're all communicating with each other. So I'm gonna show you a little
bit about how that works. The red cells here are B
cells, green cells are T cells. We're looking at the same organ,
you know these are a couple that are slices through and
then you can render that on FASP, but of course
it's a three-dimensional so I'm trying to get you the sense of the three dimensions. And it looks like this may
not, oh yeah it plays, good. So this is sped up. But I hope you're recognizing
something immediately, is that these green T cells are crawling around a lot
faster than red cells. And the reason we think that
is, is remember the green cells have to survey surfaces to find
those peptide MHC complexes. To find the bits of the world at large. So it requires that your immune system is basically crawling around
your body all the time looking for stuff. And most of these T cells
will live a fruitless sad life where they never find what they want, what they're made for.
(audience laughing) But that's good for us if they never find what they're made for 'cause
that means we're not infected. Whereas the B cells, because
they're waiting for things to come touch them, seem to
be able to just hang around in their little zone
and wait for a bacteria to kind of come challenge
them and hit them. So we have these, you
know you have some things that represent the desire
of the immune system to kind of catalog you and recognize you that you can see in real time here. Okay, so I'm bringing up something about the immune system that's important, is that it has these
feature of being motile. It's gotta really survey your whole body. If a given T cell is against or a B cell is against something that
is possibly coming in through a cut in your arm and that T cell always lived in your leg, it wouldn't be able to see it. So what your immune system needs to do is constantly recirculate. And it does that in two ways. One is it uses the blood supply, so you know, you've got blood
vessels coming through you. The reason we can even
look at white blood cells and immune cells is because they're using your blood supply as a highway. So when you have blood drawn, there's red blood cells and
there's white blood cells. The red blood cells, the ones
that go through your blood carrying oxygen, you know about all that. The white blood cells
are your immune cells and they're basically
hitching a ride in the blood to visit other parts of your body, okay? So when you have a reaction too, you also find that there are more and more white blood cells in your,
just like your glands are bigger, there's more
and more immune cells in your blood because
they've been mobilized in order to figure out what's going on and many of them are expanding. But that's one highway. There's also a set of
highways that you may not know as well that are called lymphatics. And lymphatics are important because they serve two functions. One is to take the cells
back out of the tissue, but their major function in a lot of ways is to have fluid recycle. So all the time that you guys and we're sitting here right
now, our tissues are leaking, a little bit of water is
leaking out of our blood vessels and into our tissues. And if we didn't have
lymphatics, we would swell up. So for example, diabetics have this issue, is that their legs swell
up because their lymphatics aren't working very well. But the lymphatics basically
acts as another set of vessels that drain you. And in the course of draining you, they don't just drain the fluid back out, but they drain the fluid
through the lymph nodes right? So if your arm, a little
bit of fluid comes out into my hand right now, the
blood vessels leak a little bit, that fluid is slowly percolating back up through these lymphatic vessels. And as they reach like my
arm pits or my nodes here, they reach little bubbles. These lymph nodes are basically
little balls, bubbles, and the immune cells
sit there and they wait for stuff that's coming
from the tissue to return. And if I've gotten a cut, like
maybe I just cut myself here, the bacteria and a lot of the things are just gonna slowly percolate
and go to that lymph node. And so it represents a very
nice way to survey your body. You've always gotta
recirculate this fluid anyway. Lymphatics exists as this little node where all that stuff can pass through. So all the cells have
to do is go lymph node to lymph node to lymph
node and they can basically end up seeing any sort of major thing that might happen to you right, because that's gonna drain into them. And you have a lot of
different lymph nodes they have to visit, I'm just
showing you some of the ones. The tonsils for example, you have removed, are also lymph nodes by another name. The ones in your neck
are called lymph nodes. There's ones in your arm pits. Some people that might have
had when you were a kid, the kissing disease, mononucleosis, thank you very much. Mononucleosis, you will remember having very, very big, you know
like balls right here or in your arm pits, those
were the lymph nodes again that have expanded like crazy. So there's one right at
the joints by your legs that are prominent. And there's also ones that are in your gut that are draining your intestines. So just to give a sense of these, I just took a couple of
pictures from an online source. For example, so there's
an axillary lymph nodes that drain all along your arm
pits and there's also ones all along the mesentery, so
this is the small intestine. And all along that there is mesenteries that's connected tissues
that kind of holds the loops of your gut together. And they drain, your
mesentery drains fluid out through the lymph nodes again. And then ultimately, all your lymph nodes converge on the portal
vein and rerelease fluid back into your blood
stream so you can reuse it. So this is just an example
that there's a few of these that are called Peyers Patches, that are literally little bumps here, expanded out, that are
along the small intestine. So again, there's a lot
of places in your body where they're little kind of bases where your material through
your body is draining. Okay, so I took some
time to introduce B cells making antibodies and T cells
that sort of sees things on the surfaces of other cells. A few of the other kind
of cells we call Adaptive. Adaptive means each one has a role in recognizing something that's foreign. We also have an immune
system that's more ancient, that's part of the whole system, it's called the Innate Immune System. And the ones that I mentioned already are the macrophages. These are cells that are just out there and are gobbling up things. Particularly if you see
bacteria, they'll gobble it up. Dendritic cells are another form of that, they just are called that
because they're macrophages with this very pronounced
dendrites, little arms. A couple of other ones you might know, mast cells are the ones that's responsible if you eat shellfish
and you get a response. Mast cells basically are
lining all over your tissue and they're full of really bad stuff that's meant to kill worms. And many of us in this
country don't experience worm infections, but most of
the rest of the world does. So mast cells are there and their role is to degranulate and spit
bad stuff when they see it. And so it just so happens
that you can get responses to such things as shellfish and then all the mast
cells across your body will all of a sudden say
there's some bad stuff going on and they'll degranulate
and that causes hives. A few other cell types that
you may recognize the names. So this is kind of a more
ancient immune system and this is the one that
we think of as having the ability to see patterns. And I'm gonna introduce
that really quickly. So this is a primer on what
we call Innate Immunity. So neutrophils, macrophages,
dendritic cells, these are some names for this. They can all recognize patterns that initiate their response. So remember how I said
that B cells and T cells are seeing things like
proteins and peptides, they're seeing things in the world using their special receptors? Well these kind of
cells, these innate ones, use receptors on their
surfaces that see things that are common to certain microorganisms. So for example, RNA viruses are defined because they're coming into
your body carrying RNA. You don't normally have
RNA really in your cytosol in the same way that you would when a virus comes in. And so you have sensors in
your body that are like, oh, there might be a virus present. It doesn't know which virus,
it doesn't know the sequence of the virus, but it just
recognizes that there's RNA where it's not supposed to be. You know and how your cells
are compartmentalized, the DNA, the nucleus, the
RNA's in certain places. There's also receptors of
many of your cell surfaces that are for whatever we
call pattern associated molecular receptors and
these recognize for example, the very common cell walls of bacteria. And again, your innate cell doesn't know what kind of bacteria it is,
it just knows it's a bacteria because our cell walls
don't have that component. So I want to introduce them, we call these innate cells. And so these are just gonna
be out there gobbling up things that they see that have a pattern. So you've got something that's very simple and very complex. And so I refer to this idea
that your immune system is really an information system that's collecting information all the time about every cell in your body. And it could be looking
for different things, including for example,
they're cell like neutrophils that just generally sense
the pattern of damage if your cells spewed out their content like a sea cucumber or
something like that. You know the material that's spewed out, neutrophils go oh there's some damage here and they sense that as a pattern. I mentioned these pattern receptors for bacterial cell wall component, neutrophils and macrophages can see those and they'll eat them. And then I mentioned
the ideas that T cells see these little peptides. There's that kind of
information that may be produced by a macrophage that ate something because it saw a pattern. And so then it's gonna produce a peptide that a T cell can see on its cell surface. You also have things like
things that B cells can see. So insult to your body can be in all kinds of different forms and you've got cells to sense all that. So I want to show you
a little bit about how the innate system is a
sentinel for your system. This is basically a thin
portion of your skin that is mostly skin. It's mostly the protective barrier that we associate with skin. But the immune system is there and I just rotate this around. Each of these is a kind of a macrophage or a dendritic cell that
you can see as this rotates that they're kind of in a
meshwork, they're spread around. So most of the black space is the stuff that your skin is supposed to do, that is provide you a barrier
against the world outside. But your immune system is sitting there, you know like covering every square inch with little feelers that
are looking for patterns of what's going on with
you and the world outside. So the basic idea, like if you get cut, and I'm coming, don't worry,
I'll get to the aspect of this, it fits into cancer. But when you get cut, the basic idea is that these cells that I just showed you is Innate Immune Cells,
might see the bacteria, that might come into the cut. They will capture that because they have these pattern receptors on their surface. And they can carry that on the lymph and end up into a lymph node where they can be presenting peptides, meanwhile they've been
sort of digesting that and they can present peptides
or that little bits of it to the local T cells to
get them all jazzed up. The T cells then divide
and go into the blood and then they can come back
and protect this tissue both now and in the future. And that's kind of a primer on the idea about how your immune system
probably is meant to work in the context of the
protection that you know about. So I'm just gonna show you a
little bit about that reaction 'cause it's something that we visualize and I think it's very
nice to see it this way. So this is a lymph node. The green cells here are innate cells. Many of them have
trafficked from local tissue and both the red and the blue cells are different kinds of T cells. And as we play this now, you can see all these dendritic arms. These cells want to be seen,
they're showing off their arms to the rest of the immune system. And the red and the blue T cells here, the red ones are ones
that we labeled with red because they're
recognizing their antigens. They stopped and formed interactions, so they're not moving anymore. And the blue ones are cells
that can't see that pathogen or the foreign thing
that we put into the mice and so they continue to survey. So your immune system has
like all these components and they're all like individual agents. Again the red cells have like figured out the green cells are showing them stuff and the they stopped to have a chat. And the blue cells are still
looking for what they want. And then yeah, if you're lucky, most of your cells are always blue cells, just looking and not seeing any danger. Okay, so we come back to this idea that everything has to
be a sort of interaction. I'm gonna go past this
because I want to emphasize one more thing as we get
into the context of disease. Which is again, the idea
that the immune system is embedded in your tissues. And we can reveal this by taking something like a whole lung and we can image it and so you can kind of get
the sense that we did this like your iPhone does. We took a panorama of a
whole bunch of square tiles where we imaged through
the lung at this one spot and then we moved over a field
and took the next one over. And so we can take that data in a computer and rotate that around for you. And so this is the large branching airway, this is how you breathe, the
air kind of branches down into the smaller and smaller units. And here we've only
labeled the bigger airways. I'm gonna peel this all away for you so you can get down to a
single layer of this tissue and then you can see
some of the other views that you're used to. So this is an airway, a
small-branched airway. And then these little dots
are individual nuclei. That was a blood vessel
just there that we passed. And all these little holes
here are the alveoli, the air sacs, just in
a single cross-section. So this is a cross-section of
a few that are close together. This is a top of one, for example. And if we put dyes onto that, so for example here we
put dyes that were labeled along epithelium or the immune cells. You can again see this idea that there are all kinds of different
immune reactions going on. By the way, this is a
mouse that's breathing so that we can watch it. And you see the green cells
that shoot through on the blood as we're gonna transiently
survey your lung. And then you see these little green guys that are stable in there. Those are called alveolar macrophages and they just sit there and they hope to, you know we're breathing
in particles all the time and they absorb those and
mostly they just digest whatever they see. So I'ma just give you a sense of the idea that right now you're being protected by a system that just innately
is cleaning up your body. And I think that's the next
theme that I want to get into is the idea that the
system is not just there to protect you against things, but at some point it's keeping the peace. It's making sure that
everything is more or less as it's meant to be all right? So the big reveal is that
now that it comes back to cancer and disease is
that from the very beginning innate and adaptive immune cells can live permanently within tissues. So I showed you this movie before, but what you should now remember is that, you know I've told you
about this lovely concept of immune cells that
go from your periphery to your lymph node and
they make reactions there when you get a foreign pathogen. But your entire body, as I
just showed you in the lung, is just always populated with
the immune system as well. And that immune system is
there keeping the peace for the tissues as a whole. And I'll get into a little bit about that. So I'm gonna tell you
this story a little bit about how we came to some
of the recent advances in immunotherapy of cancer. Now with the backdrop of this
and then we'll expand out into other diseases and
back and forth to cancer for the rest of the time. So you know I told you about these T cells and for a moment let's just
call them the executioner. They're the ones that
actually do a lot of the work in the immune system. They produce cytokines
and things that destroy foreign organisms and
then there are these cells that we didn't talk about, the phagocytes, that we're gonna think
about as instructive 'cause they can provide peptides of bacteria that they've
eaten or foreign organisms. So, in about the mid 90s I was studying this kind of reaction
and we knew of a receptor on the surface of T cells
that are not too curiously, was called the T cell receptor. It's the receptor that sees
these peptide complexes. And we knew at the time that
those turn T cells on, right? So that was an important feature, 'cause that's how T cells get activated. They see their peptide
ad that turns them on. There's intracellular
signaling that goes on and it's kind of a longer story there. But at the time there were
all kinds of other molecules we didn't know what they did. And it turned out that
I started to study one that was called T cell
4, that over the course of graduate career, I
realized that its function was to turn T cells off. So the immune system
always had a set of brakes that was able to turn it off. And once we kind of realized
that, how it made an antibody, it turns out antibodies can block things just as much as the
immune system uses them to detect stuff, we can use
them to grab whatever we want. And so I was able to get
an antibody that would grab this receptor and prevent
it from seeing the molecule that would normally be
turning the cell off. So if you think about this,
this is a double negative right? We can block a negative signal. So blocking a negative
signal means basically make this positive signal
the only game in town, right? So now, and this is called
Checkpoint Blockade, this being the checkpoint,
this is the thing that the cells are using
to check their activity. Now the cell is more active right? And I'll tell you a little bit more detail about this in a moment,
but the net result is, you know 2016, this is a
friend of mine actually. This was his scans essentially and this was a tumor mass
that's adjacent to his lungs and this was after six
weeks on these drugs that, that was completely melted. The immune system had
infiltrated that and destroyed that entire melanoma metastasis, simply because this reaction
was all going full boar. And really, I'm gonna break
that story down for you a little bit in terms of the science. So again, T cells surface. I'm gonna tell you this story
from another perspective. T cell surface, T cell receptor, those peptide MHC complexes. These are some of the molecules we knew in sort of the mid 90s. New molecule CTLA-4 comes along, do this reaction where we
say okay, if I treat a T cell with a trigger that triggers
the T cell receptor, it's called CD3 here, give
it a constant amount of that, we could give it a signal called CD28 that would make it go better. So this is tittering in
CD28 and the bars represent how well the T cells go, so
they get better and better. In this axis, we put in
the inhibitory signal, the one we now know to be inhibitory, and we can turn the cells back off. And so think about this,
this is the equivalent of knowing that your immune system is like a European shower that
you can turn a single dial and go from you know cold to hot. And if any of you have been
in any crappy European hotels, of course you know
there's like a fine line between frigidly cold and
really hot, it's like that. But the immune system has
a little bit more control than that, they have a
little better thermal control and basically this means
that you can dial them up and you can dial them down in the lab. And what was really nice about this story was that within about a month
of doing this experiment, I did this experiment, which was basically to look at T cells expanding. This axis here is the
number of T cells in a mouse versus days post injection
of a vaccination. And you can see after you
vaccinate your zero hours by about 48 hours, the
cells that expanded, that's the immune system
getting all jazzed up to the vaccination. And then over time your
immune system rests down and it's about two or three
times as dense as it was before you had memory within there though. But this was when we blocked CTLA-4. We could get the immune
system to go twice as high and remain high longer. And that was just through a vaccination, so that really motivated
us to go at a mouse model where tumors grow and kill the mice in the course of about 20 days here. But when we blocked CTLA-4, in other words made the T cells go higher, basically the immune
system rejected the tumors so the tumors melted. They were already growing at
this point when we inject, you can see we're injecting right here. The tumors are already growing
and basically those tumors go into a sort of a
long state of remission. And you know that took about 17 years to go from this result, 'cause
no one really believed this at the time, to the clinical results. And I showed you earlier,
this is the clinical asset that represents this. And again, this may not look like a lot, except that most people
that have this disease are dead by here, and so here's 20% or so, 10 to 20% undergoing this
study, survive with this drug, the one I'm showing you here. And this is a second
generation version of that, this is two drugs together
that do the same thing. And again, you're getting
about 50% of people that go on to die of other things, which is called a cure. (chuckles) So we cured cancer. All right, so these are really exciting. This is a real excitement
because it represents a whole new idea about
how to treat cancer right? Here the idea is, you don't try
to attack the cancer at all, you make a drug that rather
than trying to find the tumor, it doesn't care about what the tumor is, it recognizes the immune
system can help catalog that. It's got all kinds of ways
to see the different material and all you gotta do is
you gotta boost it up. And so you get these results. And I'm just giving you,
these are approved now, so these are two different drugs that together can give
you pretty good responses. And I'll show you a little bit more about different diseases in a moment. And then there's people
that don't respond to those, even now, and so that's
what we're gonna spend most of the rest of
the talk talking about. It's like why did this happen? Why did the immune system do this? And why does it do it in
some people and not in others and what can we do about that? And how does that relate to
disease even beyond cancer? Okay, so we call these
people non-responders. And if you take a disease like melanoma and here I'm just showing you the data for one of the two drugs, so that's why these
response rates are lower. But for like melanoma for one
drug, not the two combined, it's about 25, 30% of
the people respond great because without this you
know like very few people were living at all. Non-small-cell lung cancers, roughly 20% of people responding. Some gastric cancers, some urothelial, some, I'm sorry this was head and neck and this is non-small-cell lung cancer of two different variants. You see different response rates. So you these, a lot of
cancers are starting to show responses to this, but I give you now the responses of colorectal cancer. Colorectal cancer of
the majority of patients is this kind that are called MSI-low. So really only 5% are these
people and nobody responds. So here is a case of cancer
not being the same right, there's melanoma, some people respond. So we have this class of
people that are non-responders. We have this class, which turns out to be two types of people
that are responders. And then you have a disease
like this where nobody responds. And so the question is, what
is this really telling us about cancer, but also what is
it telling us about the role of the immune system, your body? And to explain this,
this is why I titled this about other diseases, even
though we're gonna focus a lot on cancer. So I'm gonna tell you
about the immune system as we're now understanding it. I'm gonna put it all into one slide. So I've just shown you
how the immune system has a big role in cancer
and five, 10 years ago, people would have said you
have to attack the cancer. The immune system is not gonna be useful. But there's a few other
systems that have revealed themselves to be really
intimately involved in the immune system. And I think they're gonna make you think about the immune system differently. So the first one I want to
talk about is your brain. So if you did not have an immune system, and I don't know if you're gonna remember this talk in general, but if you did not, you definitely would not remember this. And the reason is, that in your brain, each of your neurons form
somewhat on the order of a thousand different
connections to other neurons. And that forms the circuitry of memory. If you want to form a really good memory, it turns out that two
things have to happen. One is that one of those
synapses get stronger as a result of the experience you have, but other of the synapses
actually have to slowly degrade. So you reinforce some
circuitry and imagine you make all the circuitry when you're born and some of it's not even really used. But then you start to
reinforce certain connections and other ones have to degrade. Those are two obligate forms
of how you form memory. The degradation is done
by the immune system. So the reinforcement, you know the neurons find each other and they touch each other and they make better
connections as you form memory, but the pruning is done by macrophages, so the immune systems
I was telling you about that see bacteria, they also
have pattern recognitions on their surface that see your own cells and help prune you right? So your brain all the
time is being pruned, you know little things are going on as your immune system is going along and clipping wires that don't
need to be connected anymore. And that's how you form memory. So that, we didn't know that 10 years ago. You know if I told you that 10 years ago, people would be like oh
no that can't be true, you're missing some side bar, but it's really clear now that the immune system is doing that. And the other side of
that is that Alzheimer's is a disease now that's
very much understood. The same cells that do the clipping, cease to do the clipping. So as you get older, for
reasons we don't understand, these cells are called microglial cells and they're macrophages of the brain, they cease to do that effectively, they start to accumulate in large numbers, but they don't really clear
the material in your brain. And that's really seems to
be the number one indicator of some of the forms of
dementia, including Alzheimer's. Again, so this is a case
where your immune system is not what you thought it was. It's not just a system that defends you, it's a system that prunes you. And it can prune foreign
things extensively, like killing them, but you,
it does it more gently. Another example of that by the way, I was mentioning the
mammary, you know the fact that in mammary your mammary ducts branch. Well when women go to lactate, that branching becomes more extensive. That's the development of lactation. And that branching is
achieved by the immune system helping the branches
form, and prunes them, and makes the branches what they are. So again, it's a function
of your immune system that's not about defense, it's about making your
organs work well okay? So neuro degeneration of
the brain is a really, I think is one that
just points at this idea that you really didn't understand what the immune system was about before. You thought it was all about defense. But one way of thinking about this, is we go back like think back, I think it's about a billion years. You probably wont
remember, I don't either, but cells were in a big, you know you had individual protos that were in a stew we
think and all of a sudden we started to have multicellular
organisms like our own. What had to happen at that point? Well on the one hand you had to make sure that something wasn't eating you, so that's the immune system
that we kind of understood. You got to make sure
that you defend yourself. You also gotta make sure
that you can get along. And so the junctions you want to have to make a tissue work, it
seems like the immune system may have evolved at that point. Not only to defend you,
but also to take parts that weren't quite synonymous
and make them work together. Another really classic one
that I want to point out, just in the passing is arteriosclerosis. So in particularly our parents' time, the idea of plaques depositing
in your blood vessels were all about diet. And so you were told not
to eat certain lipids. And that's still true, diet
does have a big effect on it, but if you look very carefully at, or you don't have to look that carefully at atherosclerotic plaques, underneath them are angry macrophages. So the plaque deposition is in part because the immune system
that's normally meant to help you with metabolism,
how to deal with lipids in your body have actually gotten upset. And we're not exactly
sure why they do that and why they do that more with age, but it's clear that
arteriosclerotic plaques are immune fossae. Underneath that, all that lipid deposition that gums up your vessels
is an immune reaction and it's an immune
reaction because presumably the immune system normally,
well we know the immune system normally is involved in
helping you to digest some non-digestibles in your body, including lipid metabolism. So again, this a case where
you kind of didn't really necessarily understand
what your immune system is all about until we start to
see it showing up everywhere. Cancer, as I've mentioned, obviously things like autoimmunities, but the one that's really
I think very popular and very obvious and I mentioned
it already a little bit is the idea that in your gut
you have 10 times more bacteria than you have in the whole rest, cells in the rest of your body, and you need to figure out which of those are commencels and which
one might be pathogens. So commencels mean you
need to actually make an immune response and recognize that, that bug is a good one, figure out how to accommodate it, and then if another one
comes in that's trying to break through the barrier and eat your gut from the inside, you gotta defend, right? So that distinction represents,
you gotta know that, you gotta call one of those kind of self. You gotta recognize its peptides and you gotta make B cells against it, but instead of destroying it, you just want to quarantine it. You want to keep it, as long
as it's in the gut, it's good. If it starts to come into you and get into your blood stream, it's bad. So you need to quarantine, you need to also kind of
categorize the world at large and it's not just about
blowing everything away right? Okay, so how do we study these? I'ma tell you a little
bit about how things go on in the lab to understand these. There's a little movie that my lab made about the process. The most important way to understand this is to start to catalog
how the immune system is working in all those other settings. Say okay, evolutionarily we
had this goal of getting along, of making our tissues work together. So how are the immune
system's arraying themselves in that setting to that the cells all do what we want them to do? So this is Gabby, who's
a technician in the lab. And she's just come from the OR and she's gotten a piece
of a biopsy material, so that's a piece of a tumor. And we typically do
things like weighing it and then we'll mince it up because what we're ultimately trying to do is to release all the
cells so we can understand what they are and what
they're composed of. And she walks through the lab here and she basically puts on it, what's a glorified bread maker. It has the same chip in it actually that runs your bread maker. And it stirs that cocktail up for a while with some enzymes. At the end of it all, most
of it has been degraded, so she spins down the
cells in a centrifuge so that they become a pellet. She re suspends them and she puts them on a very elemental counter
that counts the cells. And then she's going to add a
series of antibodies to them. Here antibodies are being
used as little markers, because remember their very specific and she can split the sample into a whole bunch of many samples and put different markers on them, and then run them through an instrument that's a called a flow cytometer. And she can essentially count
all the different cell types and all the different features of all the different cell types that were from that original tissue. And each dot showing up on the graph there on that little screen was actually a cell. And it represents the idea
that what we're trying to do at some point is we're
trying to figure out where your immune system is the same, like for example in autoimmunities, it's using the same tricks in autoimmunity that it actually should be using in a bacterial infection
to get rid of the bacteria or viral infection to
get rid of the virus. At what point does an immune system have a limited number
of tricks that are meant for getting along, for
getting rid of things, and at what point can we harness those to do the thing we want them to do when they're not behaving properly. Like for example, in disease. The way we're doing this as UCSF involves, like I just showed you, biopsies come in, it can be blood or it can be tissue, and we essentially have
this, we call this, what you just saw with Gabby, we call it Diseased Biology Group. The idea is that this
at one point a disease, but it's also biology. And we need to convert one to the other. The disease is what's
coming into the clinic. Biology is what's taking
place in the tissue that we can start to think of
as how to intervene in that. So there's a lab that
basically helps to do that. There's a flow cytometry lab, that's where you saw the tube
going up in the very end. That's the instrument
that allows us to count cell by cell using
basically an inkjet printer that goes by a laser and
we can watch each cell come through the flow cytometer. We can also image that whole tissue I've been showing you a lot of images. We can do genomics on that, so we can study the gene expression. And the basic idea is to get
this huge multi-dimensional ray of understanding of
what the immune system is in that piece of tissue. And what this amounts to,
and I think many of you heard the term big data used. For example, if you go on Google, if I were to click on Google right now, most of my keystrokes are being logged. So sorry to ruin your evening, but most of your keystrokes are logged and sometimes anonymous
and sometimes not so much. But the idea there is that
by noting the things you do, they can classify you, and they
can advertise to you right? So it's a very, it's a
very straightforward thing. Maybe they can give you better
information the next time and that's a very noble cause. But the basic idea is they classify you. So you'll notice if you go enough and if you look at really dude stuff, like razors and whatever,
you'll get advertised lawn mowers and jeans. And you know if you do
perfume and whatever, you're probably gonna get
advertised things for, so that's a simple idea of classifying you by gender or gender stereotypes. But that's ultimately
the same idea of big data that we're trying to do here. We're trying to figure
out how the immune system might be similar in some cancer patients and different in other cancer patients. And why the drugs work in some versus doesn't work in the others. So I'm gonna show you a little bit of how that data unfolds
through this process here, so we're gonna be taking
many, many, many specimens from different kinds of diseases and we're taking them through this pathway and then we're studying them. At the end of the day, we
create a pretty big data base, so we can understand one disease. But we can also think
about how the immune system is taking patterns from other diseases or from other kind of left-field settings as a way to start to template
the cures of the future. So one way we do this is through imaging and I've sort of already described this in the idea of making
movies to look at things. I've showed you the one before. This is, at the lab level, this represents something
that takes on a quote that my father sent to me at one point when I was telling him what we were doing. So my father's a musician
and a music historian and he sent me this
quote from Gustav Mahler, he wrote about a symphony
that he was writing. And this is a note to
his brother and he says, "I want the symphony to
be, represents something "like the dancing figures
in a brilliant lit ballroom "that you look to from
outside and you can't, "you're far enough away and
the doors are closed maybe "and you can't hear the music. "And at that point, all the
movements would seem senseless." Well that's essentially
what happens when you image as you see stuff and you have
to infer what's going on, but at the same time you can sort of make very good calculations. And so I'm gonna show you a movie in the last 10 minutes or
so that represents a huge insight for us in terms
of all kinds of things about I just told you about, okay? So this is a movie that we
collected about five years ago and I showed you this in
still in the very beginning. The black area here is a tumor. And the yellow and green and orange are all forms of inhibitory innate cells. So cells that remember the innate cells are the ones that recognize patterns. These guys surround the tumor
and they recognize patterns and I call them inhibitory
because they turn T cells off. They present peptides to them
and the resulting of that is that they turn T cells off. But there's one little gem right here of two little stimulatory dendritic cells. This is not a very frequent
little field of view, but I've obviously trimmed this because it's gonna be able to show you that the immune system's got
some good stuff going on, even when it's mostly bad. So there's a lot of
reactions like the one's that s gonna play out here. The T cells are in blue,
and they're interacting with a lot of these inhibitory
myeloid populations here. So we watch these like
Mahler would have wanted us to watch his third
symphony and many others. You say oh, now we're
starting to understand actually that music behind this is that these cells are
turning off these T cells and that's dampening
down the immune response so that you don't make a response to tumor even though you've got the T cells there. But this little reaction here is a gem. And the reason we know it's a gem is I don't know if you notice
the difference in the blue. The dye that we used to stain the T cells turned out by complete happenstance to change color just a tiny bit as T cells got activated. And so as we were
watching this we're like, well that's weird. First of all, there's a
little reaction going on there and second of all, the T cell color is a little bit more
blue, a little less green. And so we started to wonder what that was and we realized that this
is a stimulatory reaction, here the immune system's being turned on against the tumor, here
the immune system's being turned off. Most of what you look, if you
look across lots of movies, most of what you'll see
is what you saw here, this sort of inhibitory reaction. And very little it what you saw here. But it's a little bit like
trying to get a squirrel to come out of the hole. We've identified a squirrel,
it's a really good thing, and it's not very much of one, but it turns out to be the
immune reaction you want. And instead of what we want,
most of what's happening when people come in the clinic
is this inhibitory reaction. All right, so we can
measure this by this method I call flow cytometry. So we can count a lot of the cells. I'm gonna jump ahead a little bit, but the good read stimulatory cells and the green, yellow,
bad inhibitory cells can be counted because
we can use something that's sort of like an inkjet printer, it's called a flow cytometer and instead of ink we're putting the cells that can't be digested into that and as they go past a laser, we can read out all
kinds of details of them, we can continue them. And if we do that and we look at them and this comes back to metastagnon, if we look at people
that are non-responders versus responders and we count the cells that are in their tumor micro environment, we find out that the
cells that I showed you, those red ones that are
nucleating that good reaction that we happen to notice,
the blue dye changing color, those people that have
lots of those cells, so this is the number of cells
that they have on this axis, they're the responders. We group people into
responders and non-responders. And people that don't
have very many of those are the non-responders. So we're starting to say,
hey we've got two biology as we saw in that movie. It's really important because
having the good stuff, the ones that are turning T cells on is associated with people being able to get their immune system going. The immune system's got
something to build on. The little squirrel can
be coaxed out of the hole. Whereas in the non-responders, you don't have very much to go on. You've only got that
inhibitory system to work with. Turns out that you can
basically build on that and you can say well why
do you have the good cells that are making the T cells good, those stimulatory cells. And it turned out that when
we looked at all our data more and more carefully, a little bit like Google mining theirs, this axis here shows the
number of the good cells, the ones that make the
immune system go forward, those innate ones. The red cells that are making
the blue cells turn bluer. And this is a number, this is a cell called a natural killer cell. And there's a nice linear relationship. There's a melanoma, this is head and neck. Head and neck is ridiculous,
the P value is .98 and it says that it's 91. It's a very high correlation
between one population and the other. And it turns out, and this is
a kind of a complicated graph, but I'll try to explain it to you. That if you take a bunch of patients, this is like 20 some patients, and you categorize them
as a non-responder, you say okay, three months later, who responded to my drug? I'll call them a zero here versus a one, who's a responder or a green or yellow. I can ask what cell
populations in their tumor are associated with that. And the two cell types are
that cell that I showed you in the top right of the movie, these are these dendritic cells, the red one that I showed you, making a good immune reaction. Here are that NK cells that I showed you that correlate with them. Red here means that the
patients have large numbers of the cells, so you
can see the responders. Typically you have large
numbers of both NK cells and those good dendritic cells, and non-responders,
you're in really bad shape if you don't have either
of those populations. So cancer patients are not the same because their immune
systems are not the same. We're treating them with an immune drugs and we need to understand the system that really is necessary for them, their immune system to get going. And it's that one that I
showed you in the movies. It's the interaction of
those good dendritic cells and it turns out there's
some NK cells here too. This creates what we call an archetype. So as we study this, we're
understanding immune system gets a bunch of its cells together and makes a group that can do good things. So I've just told you about one here that's these NK cells that turns out they work together to make
these good dendritic cells. The good dendritic cells work together with CD8 T cells so when they
come back into the tumor, they all work together
to destroy the tumor. And so this represents the
idea that as we build up our understanding of the immune system, we start to see collections of cells that represent an axis. And that axis, we're
calling it an archetype. Such that if you look at
all melanoma patients, about 40% the people that
respond have this axis that represents good innate cells and they have a good adaptive population and they basically have other cells that go together with them. They generally actually survive
even well without drugs, compared to most of the population. But we have people that we understand that they have a different immune biology than the patients that don't respond. So in the interest of time,
I'm gonna go past this, but I'm gonna point out to something that some of you with eagle eyes might have noticed, is that
there were some exceptions to this rule I told you. And it basically comes down to the idea that there's some patients here that respond for a different reason. They have a different set of immune cells that helps to protect them. So here's the patients that
have sort of the archetype I've just described, the good innate cells and the good NK cells
and the good CD8 T cells. There's a population over
here that has another kind of immune cells
called CD4 lymphocytes. They have a different
kind of dendritic cell that's down here and so you have the world dividing itself into two patients. The population will need to go again because time passed this. Just to point out, you
start to see patients in different balls. Even though we're calling them all cancer, that their immune systems are different. These people are very lucky, they're treatable by our drugs, there's a portion of these other ones that are very lucky, they're also part of that green population
I was just showing you, but then we're starting
to see these other classes of patients that have
different immune compositions. And that means that they're responsive. We don't have anything to build on. So that's important because
we can start to place those into different indications. We can say okay, so some
diseases like melanoma have these two good classes, but maybe in head and neck,
we only had one good class and we have a bunch of bad ones. All right, so we start
to understand immune, you know cancer not as
a disease of origin, but really as the disease
of the immune system. Like why isn't the
immune system protecting and how is it protecting
and what is its assets and what are its liabilities. So this comes back to this question, what to do for the non-responders. And I'm just gonna show you one thing that we've been doing and a
company that's an off shoot from UCSF, that I hope you'll understand. Is that in general if we
look in normal tumors, we find not really enough T cells. We find too many of the
inhibitory populations of innate cells that I told you about. Yellow cells here, sorry the
bars are different colors that what we've been seeing before, but the yellow cells are
the good dendritic cells, the ones that I've just
been telling you about that they're really associated
with good prognosis. We've been able to find
drugs that basically lower the burden of the
inhibitory immune system, so lower the number of
these red bad cells, maintain the number of
the good yellow cells, and bring in more T cells. And those drugs take
basically non-responders in the case of tumors and we're hoping in the case of patients
now where the tumors are growing out and
convert them into cures. And so the idea of this
is to really repurpose the immune system and take
advantage of these things. And this brings me back,
this is the last slide. I'm gonna open up for questions here, to this idea that the immune system, really it's not what
you've been thinking it is. It has a really intimate
ability to recognize cancer because cancer is a disease
in which the immune system is present just as the
immune system is present in all your tissues. And as we understand these other diseases and in fact if we understand health, we also probably have the
templates to treat the cancers that we don't currently treat. Namely we have understanding
of what the immune system is capable of doing and
really what it's made to do. And I would say that we're
just breaking that open right now, but it's a really exciting time because we've already shown with cancer that we can leverage it. We can figure out what its assets are and we can put them to good use and we can figure out who's gonna respond and now we're in the course
of figuring out of course, as I just showed you, how to
treat the people that are not. So with that, I would be
happy to take questions or in fact to kind of
discuss any of the ideas that have come up over the last hour. So the question was, can you introduce additional T cells into the
body in order to jump start it or maybe to improve it? And there is a whole
therapeutic series of trials that are going on utilizing
either a patient's own T cells that have
been expanded in the lab, it's called autologous T cells transfer. Autologous, meaning from the same person. But there's another variant of that. It's much more an engineering approach that is called chimeric
antigen receptor or CAR T cells that you may read about or hear about that involves the idea that
you take these patients, say I'm a patient. Take the cells out of me
and I put on their surface additional receptors that help that, that my T cells all become
specific for the tumor right? And then I try to put those back into me and get them to obviously
leverage the idea that the immune system then
maybe can teach other cells, okay this is a bad thing and watch out, even as it mutates,
let's watch this thing. And that's a therapeutic
avenue that's being explored. It has a down side because it is hard to get the immune system to figure out exactly how the immune system communicates between populations and
ultimately if you generate a CAR that just against one thing
that's wrong in tumor, you're kind of doing
what we did 20 years ago, you're trying to attack the tumor right. You're saying, I'm just gonna use the immune system as a drug, just like I tried to make a drug before. And most of what is happening with CARs is that the tumor is willy
and escapes by changing that exact feature that you
targeted with the immune system. But there is hope obviously,
that you'll get the cell, you bring in the cells and
you bring them armed correctly and they will teach the
rest of the immune system to see that thing as foreign. (audience member speaking faintly) Sure, yeah but what's interesting, yeah, so the question
was, that I was saying that non-responders didn't
have enough T cells. But I didn't exactly say that. In fact what you find in non-responders is they have T cells but
most of their T cells are in a state that's repressed. And here's where we can talk about something I didn't show here. One of the funny features
of the immune system is what it does with viral infection. So most of you are used to the idea that when you get a cold,
you ultimately clear it, all the virus gets killed. And that's mostly true. The antibodies you make over time, sop up viral particles and in a good world you're sterilized at the end of that, so you don't have any
more viral particles. But take herpes infection. Many people in this room
have herpes infections, CMV, herpes obviously not, the oral one is very common. And what that does, herpes
infects your nerves. It is very hard to get rid of. It is extremely, it'll go quiet
for years and year and years and then people have a cold sore right, they'll have a stress
moment and the cold sore. Same with CMV, it's a very common virus that's passed when high
schoolers are kissing. It's called, another one
of these kissing viruses. It can come in saliva. Okay, so let's take the
herpes as an example. It is sitting in your
nerves, what should you do? Well you might think let's
get rid of that, clear it out. Well what's going to
happen if you do that? You're gonna kill the neuron. So what happens to you
in evolutionary fitness? You don't have sensation,
you don't have motor, right? So if you killed every viral
infected cell on your body, you might kill yourself. Same with HPV right, HPV is
a liver virus, Hepatitis B. If you killed every infected cell that had Hepatitis B,
you get liver damage, you get liver disease and you die. So evolutionarily, it's quite possible and I think what we're learning
is that the immune system, in order to get us past
reproductive stage, makes kind of compromises and says I'm not gonna sterilize you. Instead of the virus remains quiescent, like in your nerves like the herpes virus or in your liver like most of your life if you have HPV, RCD, I will
just have an immune system that kind of accumulates
a bunch of T cells that can see that but
I'm going to keep them in a quiescent phase. I'm not gonna let them get too reactive unless the virus comes out of dormancy. And then I've got a T cell
response that's kind of, and so we call those exhausted T cells. You see them more and more, again I'm talking about how
we're seeing the immune system. We see more and more in your body. A lot of your cells have this phenotype that they aren't really,
we call them exhausted in a sense that you're
exhausted when you go home and you lie on the couch and
you just kind of feel like you can't move, but
the fire alarm came on, you'd get up right? Even if you were exhausted. So think about the immune
system the same way. Say you had a response to a virus, but you didn't wanna like,
you didn't wanna like kill that nerve. But if it comes out of
and starts infecting all your other cells then you
do, it's like a fire alarm. That's what we think might be taking place in a lot of tumors. Is that that same system that
has this kind of exhaustive quiescent has been accessed by the tumor, how we don't know, but it's essentially taken the immune system and there are lots of T cells in there but they're
in this exhaustive state. And part of that
exhaustion seems programmed by the innate cells that
we've been talking about a little bit in that crosstalk. We don't fully understand
how, but it kind of, sorry this is a very long
answer to your question, but it's a very long question
when you think about it. It's not that you don't
have T cells in tumors. I've showed you a lot of
examples where there were T cells in tumors and
those tumors were growing. It's more that the T
cells that are in there, the immune system has adopted a stance that isn't the one we want. The one we want would
be to destroy the tumor. Instead it's kind of accepting
it and letting it grow. And that's the distinction
we need to understand. That's why I point out
these other diseases. We're saying the immune system's got all these other things it's doing. And maybe tumors are
accessing those things. And to understand those things is to understand where they came from and to understand how to reverse them and then how to reverse them in cancer. So it's a very long
question, but it's actually, you're hitting kind of
the bigger issue head on. Yeah, and I think it comes back to the previous question a little bit when we think about, a tumor
has to learn two things now. I told you at the beginning,
we always understood the idea that a tumor needs to get so that it doesn't have
growth control anymore. So it loses the innate sort
of control over its divisions, so it starts to divide and divide. But the second thing we now understand is it needs to fool the immune system into thinking that it's
all part of a wound that's repairing or a
brain that's remodeling or a breast that's remodeling or any number of these
patterns that I've been trying to describe to you. That can be arrived at by right mutations. And if you give us all long enough time for all of our cells, one of them, by turning the combination locks of all the different
genes and mutating them, will arrive probably
at the right solution. Some of it might be
predestined because of genes that were already turned
at the right combination, like what Jenny was
probably talking about. Genes that are already in the wrong state because of a mutation. But then if you add mutation upon mutation among mutation, some cells will get lucky and they'll start to look
like a remodeling brain. And then your immune system can be fooled into thinking that's a remodeling brain. I just need to kind of help it, as opposed to what we'd
like to have it do, is just ooh, that's a tumor. Or that looks like a virus that
I really need to get rid of, which is the archetype
that we want it to take. So I think you're
definitely onto something with the idea that certain mutations can help a tissue look like
a particular immune state that dials an immunity in the wrong form. It dials in this get along form as opposed to the destroy me form, which is what we want it to do. That's a good question. You know there's a lot
of sort of snake oil in immunology right now. And I'll tell you two
things that are probably not really good to do. One of them is this idea of
boosting immunity globally. So there's a number of what are they, sort of herbal supplements that say boost your immune system. And if you understood anything of what I just said right now, is there's this idea that
boosting your immune system can cause autoimmunity. It's not that you want
to boost it globally. In fact the drugs that we
make are kind of in that class and we would like to get
them to be more specific. So it's a really hard question to answer 'cause I'm not sure that we know, like what do we want. Do you want a better response to viruses? If so though, you know that might actually give you more likelihood
of getting an autoimmunity where your immune system sees
everything as a virus right? And then and that can
include like your pancreas, and so you get diabetes. Or it can include various other tissues like your nerves, so you
get multiple sclerosis, which is an autoimmune disorder. So it's not, there's no right
answer to your question. But I think there are wrong answers. And I gave the example of
boost your immune system that you know just on the
face of what I told you isn't specific enough. What do you want to boost and why? What is it that your body
needs because of who you are and what your experience
is and maybe what viruses you've carried or what genes
you're carrying in your body. Another example though
that's quite important to point out really, now that the data is coming out really strongly, is there's a lot of companies that sell what they have named probiotics. So these are the idea that
they're gonna give you bacteria that are pro, they're for you, they're professional, whatever the pro is supposed to mean in that name. But there's no scientific
merit for those names. And in fact, what's becoming very clear in the context of
immunotherapies is that patients that take probiotics do much worse. And it's because one of the best things that bacteria in your
body can do is be diverse. There's some element that
that's becoming clear that you want to have, like
in all biological systems, you want to have the ability to kind of do a lot of different things. And what you do with probiotics is the diversity of your gut bacteria goes really down, it
goes towards those three, four, five, 10 that are in the pill. And so the diversity of
your gut bacteria is worse and associated outcomes are clear. On the other hand, people
that eat a cup of day of fiber and they actually get a
very diverse microflora do much better than those drugs. So there's a lot of, what
I'm kind of pointing out is they're a lot of things
that's sort of on the, if you don't think about them enough, your intuition will tell you, oh yeah, I should take probiotics. Probiotic, that's good. But it's a name right? And think about what your
immune system really is about and you'll say that's not quite so obvious that you want to do. You don't necessarily
want to only have three good bacteria in your body. What about having a
diversity of the bacteria that all have different things
to help you be healthy right? The reason you have commencels
is because some of them help you digest certain things. Bile acids, the main way
you take care of lipids, are made by certain strains of bacteria. In other words, the chemicals
floating in your blood stream, some of the most important ones are made by things that are not you. And so the idea of toying with that, you know instead of sort of just saying, oh these ones are better than those, it's pseudo science and
it's not quite yet there. Some day it will be. I have no doubt that we'll get there, but it'll also probably
be very personalized where what you need and what I need may be kind of a little different based on how we were raised, what we normally eat, what our genes are. And at the moment, again, I
can't really give you the answer to that 'cause I don't
really think we know. So, I think that's generally true. But if you look at vitamin C metabolism, in this room each of us
has different enzyme levels based on our genetics
that will degrade them at different rates. So the FDA requires you
know, it gives you numbers from vitamin, vitamin
D is a more classic one and retinol acid too. But in general, vitamin
metabolism varies a lot among the populations. This idea that there's
an FDA level of a 100% or you should have more of that or less, is also very individual. If you have the biosynthetic
enzymes to degrade those, then you might need a lot more than I do. I think it's generally
true, I think vitamin C is generally something that is antioxidant and it helps you deal
with some of the things that can be bad for your cells. But the degree to which
you need more of it, I'm not sure that we know exactly what, maybe having an orange
a day is plenty for you. And for me I need to
have a gallon of juice. So T cells, I remember
when I was telling you about all the confusing names
that we give to lymphocytes. One of them was a cytotoxic T lymphocyte. So T cells actually have the ability, when they see a peptide being presented by an image, see they have the ability to directly release toxins
into the adjacent cell, blow it up. And we think the reason
for that is in fact, and it goes back to the question asked by the gentleman in front. Is that in some viral infections you want to blow that thing up. You want to just catch the virus before it started to replicate
and just blow it away. And so the cytotoxic T cells do that. There are other cells in your body, neutrophils noticeably are ones that capture antibodies,
remember the floating free things that you make, and if a
bacteria is bound by an antibody to a neutrophil, the neutrophil
does something similar, it degranulates, it just spit all its toxic chemicals onto that
bacteria and blows it up. So in that sense a neutrophil
is also an executioner. But his actually comes to
the question behind you from earlier about boosting
your immune system. Do you want that? Well in some senses, in some
cases you absolutely do. If bacterial substances is
raging through your body, you want the neutrophils
popping those bacteria every which way. Get that going too fast,
and you start to get the leakage of blood
that is sepsis, right? So that fine line of sepsis
can kill you in hours. Right, 'cause everything just goes crazy in terms of cytokines, it's
like a nuclear bomb goes off. And your immune system is dangerous right, so this is a system that can kill you. It can kill anything and
so that's where I think the shower analogy, what
we learned with CTL8-4 is kind of important one to say, you want it in the fine range of warm. You don't actually want
to be hot all the time. You don't want your immune
system ragingly hot all the time because you'll start to
pop everything around. And you don't want it cold all the time because you won't recognize
things that are foreign. So you need it in that warm range. But maybe different tissues,
you need a little bit warmer than others and maybe
in different situations, different days, different exposures. And again, that idea of
boosting it globally, to me is a vast implication
that's just wrong because of these executioner functions. So a vast majority play
on what I showed you we did at Berkeley, this checkpoint. So most of the drugs
that are being developed in cancer immunotherapy are the idea of a molecule on the T cell surface that generally turns the T cell off and blocking that or
sometimes in a similar way, engaging one that gives a positive signal. So that's a general classical
checkpoint blockage. There are however, a few pharma companies, quite a few programs that play on some of the more subtleties
of immune molecules. And I didn't describe these in any detail, but there's a set of immune
molecules called cytokines, we've been talking a lot about how cells talk to each other by contact, well they can also kind
of, they can also release, they can broadcast their
status via molecules that they secrete. And so for example, if you get
an immune response locally, it didn't go into this great detail, but you can get kind of like a wave of these cytokine molecules
that were released out and get all the cells locally
a little bit jazzed up, right? Maybe a little bit active,
or a little bit likely to die or what have you. So in many for example, autoimmunities or rheumatoid arthritis is a case where you have an immune
reaction in your joints that is forming, it's
raging always a little bit. There are drug companies
that are making drugs that try to block those cytokines, they're blocking that general broadcast of damage, damage, damage, with the idea of trying to quell and cool things down a little bit locally, via these very general signals that are made by inflamed immune systems. So, I mean there's quite a lot of action in the immune system obviously. You can tell the cancer has really spurred a lot of people to think
about how we can access this and obviously in a case like that, there's a question of specificity. Like how do you do it so that it only hits the rheumatoid arthritis setting, but doesn't hit other places
where the immune system is using that same molecule for good. And in particular, it
also comes down to the, the woman at the back of the
audience was pointing out that she actually had some experience with some of these drugs. It depends a little bit
on the patient right? So I should tell you is
that the drugs for cancer have a side effect in
about 5% of patients. And I'll give you an example. Man walks into a clinic,
he's a 60 year old man, he comes into my friend, Mark
Anderson's diabetes clinic. And he's presenting
with diabetes at age 60. Well I should tell you that the age, the frequency with which you see people first presenting diabetes
at age 60 is very low. Most diabetes of this
kind, autoimmune diabetes, most people are about 16,
it's called juvenile diabetes, somebody that's a teenager or a youth. And he just had had chemotherapy. He just had checkpoint blockade therapy where you derepress the immune system. Turns out that he probably
should have gotten diabetes as a 16 year old, his immune
system managed to turn on these inhibitory circuits,
preserve his pancreas, he didn't have diabetes for entire life, he gets cancer, his immune
system gets derepressed, and all of a sudden the diabetes shows up. And so again, it comes up to this question that you, that happened to some people that have that predisposition
and dodged a bullet when they were younger and so you're now derepressing not only the
immune system to cancer, but the immune system that in some ways has been protective of this liability that you've had your entire
life that maybe you should have, you know your body
wanted to respond to this whatever it was about your pancreas that was telling it you know you're supposed to destroy this. It was actually able to quell that until we released those brakes. So this is gonna become a field as we start to understand it where we need to think
about the whole patient, what their genetics are,
what their experience are and what their likely side effects are, giving some of the types of liabilities that can be from genetics, they can be from experience, you know your body's
experience over the years. And you got a point or a question. - [Audience Member] Do
you think the variability in the immune system between people have been predicted a
predictive factor for disease? - Yeah I do, I do. And I think there's,
there's a kind of so far, we don't have enough molecular data, but there's been a long-standing
connections between, well one that's really interesting is this, here are the patients
that get neuro degeneration where their immune
system fails to function quite properly in here and
it gets kind of a lil jiggy and causes a disease called
frontal temporal lobe dementia. Those patients also show autoimmunities. And we kind of haven't worried
about the autoimmunities cause FTLD is much worse and
people fie so that first. But as we're understanding
the molecular basis for that, the same gene that's giving
deficits to the immune system in the brain is also
giving them propensity to autoimmunity and the cool thing there, this is like cutting data from our lab, is that, that same gene in mice, protects mice from cancer. You get a defect in it,
you get sort of heightened equivalent of autoimmunity,
which is clearing the tumor, it also predisposes to a
frontal lobe temporal dementia. Where that happens, you prefer
to have it only in the tumor but not in the brain. And so those are the tricks
that we're gonna have to figure out with drugs in the future, is to figure out you know
where some of these tricks can be harnessed locally, but not globally to make the immune system a
little bit more active here, but not there. And it can be tricky, but I think we're, and we're starting to understand
the tricks that can used. Yeah, so think about a fulcrum where the immune system can
go two different directions. Most of the tumor micro environment is pushing immunosuppression. And there's these good cells that we know are pushing activation. What we managed to do
in that particular case is figure out drugs
that specifically target the immune system that's doing suppression and leave the immune system alone that we want to rise up. And it really is as simple as that. The idea of some of these drugs is very simply, it's specificity. And here we're trying
to find specific drugs for the immune system that are specific for the immune system that's
the bad immune system. And the distinction is of
course, how do you know? And that's what we've been
trying to figure out there, and what we have figured
out is some molecules and some pathways that are very discreet and very distinct to the
suppressive archetype and leave the other one alone. And the other one there therefore becomes, it's like a weight thing
with the immune system and it at some point makes a decision based on the weight of evidence. And if you basically relieve this, then this one seems weightier. And that's how we understand it. I think we need to finish, but thank you very much for coming. (audience clapping) And I'm happy to answer
some questions from you. (upbeat music)
