Tumor Microenvironment and PD-L1 biomarker

[Music] hello my name is dr. Michael Lynch I'm a pathologist and I work on the division of medical and scientific affairs for Roche tissue Diagnostics focusing on companion diagnostics today I'm going to focus on the tumor microenvironment the cancer immunity cycle the checkpoint immunity system and the role that PDL one place in the checkpoint immunity system this is designed as an overview so that you can understand the function and role the PDL one plays in tumor biology I will conclude by briefly talking about patterns of staining that can be seen with the SP 142 ihcs a showing both the hematoxylin and eosin stain or the H&E and the IHC stain we now understand that there are different types of tumors with different patterns of differentiation in different grades and if the genetics of the tumor drives a large part of the tumor metabolism and growth but over the last few decades we've also come to realize that the environment in which the tumor resides also plays an important role in tumor growth tumor viability and tumor spread so in other words the tumor and the tissues around the tumor also play an important role in the evolution and fate of the neoplasm so in this diagram we show a variety of cell types that are often present in the tumor micro-environment there the tumor cells themselves there's fibrous tissue adipose tissue and the surrounding extracellular matrix there are blood vessels and there are multiple inflammatory cells including granulocytes in eosinophils other myeloid derived cells mast cells macrophages dendritic cells B cells and multiple types of T cells and finally there are multiple bio reactive molecules including cytokines chemokines growth factors and multiple subtypes of interleukin [Music] the Cancer immunity cycle is operational in the tumor micro-environment and it's the basis of our understanding of how the body recognizes neoplasms and provides surveillance and defense the cycle has to manage the delicate balance of recognizing self versus non-self so as to prevent tumor growth on the one hand and prevent autoimmunity on the other briefly the cycle starts with neo antigens created by oncogenesis being released by tumor cells and then captured by dendritic cells for processing essentially in the lymph node the dendritic cells then present the capture antigens on MHC class 1 and MHC class 2 molecules to T cells which Prime's it activates effector T cell responses the activated effector T cells then traffic to and infiltrate the tumor bed recognize and bind the cancer cells with the clonal expansion of the cytotoxic T cell response killing of the tumor cells it releases additional tumor associated antigens that increase the breadth and depth of the response in subsequent revolutions of this cycle cancer cells have however developed mechanisms to evade immune detection and destruction the fact that a tumor is present means that the cancer immunity cycle did not perform optimally this is where the checkpoint immunity system really comes into play so now the cancer immunity cycle has generated T cells and T cells are in the tumor microenvironment this is a diagram of the T cell and shows the multitude of signals being generated telling the T cell what to do you can see that the activation of T cells is regulated through a large number of activating inhibitory checkpoint signals that both enhance and suppress these functions and enable the T cell response to be adaptive there are a number of accelerators that can activate the T cell response but once activated negative inhibitory pathways are initiated to work as molecular breaks to suppress hyper activation of T cells and thereby prevent autoimmunity this understanding of the critical role of the immune system in cancer has resulted in significant clinical breakthroughs in recent years the pd-1 gene was discovered in 1992 when it was found to be upregulated to an epitope excell death in lymphocytes its ligand PDL one was discovered in 1999 this is a type 1 transmembrane protein that can be expressed on many cell types including antigen presenting cells lymphoid cells and tumor cells so in more detail what do p d 1 and PDL 1 actually do in an abbreviated and simplified way the T cell has two receptors for PDL 1 on its surface PB 1 and b 7.1 if either one of those receptors recognizes and attaches to PDL 1 the T cell is down regulated and essentially shut off the interesting part of this is that PDL 1 can be present on tumor cells as well as on lymphocytes particularly on what are known as tumor infiltrating immune cells again if either receptor on the T cells binds to PDL 1 from any source it inhibits the T cell from tumor cell killing them so tumor cells have figured this out in P do what is expressed in multiple tumor types is a way to evade the immune response so when we stain for PDL 1 we are basically trying to figure out whether the PDL 1 axis is present in op rating in the particular tumor that we're looking at because that is going to give us an indication of how likely the patient is to respond to anti PDL one therapy so to conclude this session let me show you a few pictures of some tumors with The Associated tumor micro-environment and the S P 142 IHC stain for PDL one so that you can see what this looks like under the microscope in this first case we're looking at immune cells that are in the tumor microenvironment if the immune cells are outside the tumor nest itself and in the connective tissue between tumor nests they can occur either diffusely in aggregate bands or an aggregate nests as a seen here so this is one standing pattern for immune cells that shows the common punctate pattern in immune cell nests that are in the tumor microenvironment adjacent to the tumor continuing with the theme of immune cells staining this case shows immune cells that have infiltrated the tumor nest itself and are now in a single cell spread at pattern so this is a second pattern of immune cell staining where the immune cells are in the tumor cell nest in this third case you can see both patterns of single cell spread within the tumor nests and band-like aggregates outside the tumor cell nests and in this fourth case we're gonna move to tumor cell staining here you can see the tumor and the intracellular stroma on the H and E stain and the IC staining is on the right this is a typical staining pattern for tumor cells where the staining is circumferential and membranous and so it resembles a chicken-wire pattern if you look closely you can also see that there is an immune cell infiltrate in the tumor microenvironment and that these cells also stain and now we have both tumor cells standing and immune single cells standing within the tumor cell nest itself so when a pathologist swedes flights like this he or she needs to take a little extra time and make sure they're interpreting immune cells and tumor cells correctly today we've covered a lot of ground about neoplasms and how they evolve as well as how the immune system tries to inhibit their growth and spread the main take-home points are these number one program death ligand 1 or PDL 1 is an immune checkpoint molecule that negatively regulates t-cell function allowing some cancers to evade immune surveillance number 2 PDL one is broadly expressed by tumor associated immune cells and tumor cells and is regulated by different mechanisms and finally number 3 PDL one expression on tumor cells and immune cells can be evaluated by the Ventana SP 142 IHC diagnostic assay thank you for watching [Music] [Music] you

Channel: RocheDiagnosticsUSA

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Keywords: PD-L1, histology, complementary diagnostics, companion diagnostics, immunotherapy, TME, immunohistochemistry, SP142, FDA approved, Blueprint, Tecentriq, atezolizumab, algorithm, pathologist, education, t-cell

Id: tdslSK9HLp8

Length: 9min 36sec (576 seconds)

Published: Fri Jun 01 2018