We use both our own and third-party cookies for statistical purposes and to improve our services. If you continue to browse, we consider that you accept the use of these.

Escape Genes Q&A with Jon Armstrong

 In Advanced Applications, Cofactor Genomics, Molecular Diagnostics, Q&A

Escape Genes and the Immune System

In this week’s Q&A, Cofactor’s CSO, Jon Armstrong, discusses immune escape mechanisms. We’ll chat about the most recent developments and how Cofactor is leveraging this knowledge for better predicting patient response in immunooncology using RNA.

Q: What does “Immune Escape” mean?

A: In 1957 Thomas and Burnet hypothesized that the immune system performs immunosurveillance, meaning it monitors, recognizes, and eliminates malignant transformations. This is really the basic tenet of immunotherapy. However, this hypothesis has since been refined to recognize that the immune system not only protects against tumour development, but also in an interesting way, selects for tumors with decreased antigenicity and/or immunogenicity and therefore helps to promote tumor growth. In this way, cancer clones evolve to avoid or escape elimination by the body’s immune system and in another way, tumors escape elimination by the immune system by orchestrating or promulgating a microenvironment inside the tumor that increases the antitumor immune response.

Q: What are some of the common genes involved in these escape mechanisms?

A: I can think of a list of maybe 10-25 if we think about not just escape genes or genes that are involved in escape, but potentially co-stimulatory and co-inhibitory genes. The major players I think of are TIM-3, T-cell immunoglobulin mucin-3, LAG-3, SLAMF4, CTLA4, PDL1. These are all of the the kind of well-known players and certainly PDL1, programmed cell death 1, and cytotoxic T lymphocytes 4 are current targets for immunotherapy.

Q: How does understanding these mechanisms play into therapy selection, or timing?

A: Well a substantial portion of cancer patients that respond to immunotherapy will develop resistance to therapy and relapse. The better we understand the immunogenetic mechanisms of acquired resistance, the better we’ll be able to develop combinations and scheduling of immunotherapy treatments.

Q: Why does Cofactor believe that taking a multidimensional approach in measuring these signals will be beneficial?

A: Scientific findings suggest that upregulation of PDL1 may define a tumor as one that will respond to immunotherapy. However, not all PDL1+ tumors are associated with immune infiltrates and some PDL1+ tumors do not respond to anti-PDL1 therapy at all. So single point biomarkers such as PDL1 are failing us as discriminators of response to therapy. It’s obvious that leukocyte infiltration into tumor tissue and recognition of malignant cells is necessary for successful immune mediated elimination. However, a permissive environment may develop. For example, immune suppressive mechanisms active in tumors infiltrated by T cells may be completely absent in tumors devoid of T cells where myeloid cells dominate. Thus, there is an obvious need for robust immunogenicity biomarkers and by layering info about the immune cells that are present in the tumor with the expression of immune escape genes, we can generate more comprehensive and predictive biomarkers for therapy response.

Q: What mechanisms of immune evasion do you find interesting?

A: There’s this protein extracellular galectin-1 that can interact with cell surface glycoproteins to form a kind of physical, lattice framework on the cell surface. When you think about tumour biology, this lattice framework could potentially form and inhibit the entrance of immune cells into the tumor. That’s interesting to me because I think as biologists and scientists, we think about these cascades of chemical signals that happen between escape genes and co-stimulatory and co-inhibitory genes. A physical barrier to infiltration is a really interesting, different way to think about it.

Questions about Cofactor or our product offerings?  Reach out to schedule a time to speak with one of our Project Scientists today.

 

Recommended Posts

Start typing and press Enter to search