Immune-modulating therapies have been revolutionary treatments for several cancer types including melanoma, lung cancer, and renal cell carcinoma. However, most cancer patients do not respond to immunotherapies, and there remains a critical need to identify alternative approaches to treating these cancers. Endogenous retroviruses (ERVs) are genetic remnants of retroviral infection transmitted vertically through generations, whose transcription can result in type-I interferon activation, and/or presentation of ERV-associated antigens. Recent studies on ERVs in human cancer has shown that ERV expression can render cells immunogenic in a variety of cancer types including colorectal, breast cancer and melanoma. Therefore, characterization of how ERV expression is regulated in cancer will reveal opportunities to therapeutically de-repress ERVs and improve immunotherapy outcomes in low antigen tumors. In the F99-phase of this proposal, I will investigate the role of epigenetic factors regulating ERV expression and anti-tumor immunity in melanoma. Specifically, I will test melanoma tumors for ERV tetramer-positive CD8+ T cells, to determine the antigenicity of de-repressed melanoma ERVs. Furthermore, I will determine the mechanism by which type-I interferon response is induced in epigenetically-modified tumors, and determine the role of ERV MHC-I antigens through genetic knockouts of each component and evaluating tumor growth and immunogenicity. This work will establish the mechanism by which ERVs are regulated epigenetically, and establish a framework for investigating ERV regulation and its impact on the immune response to cancer. In the K00-phase of this proposal, I will harness my experience studying ERVs to investigate their utility in improving the immune response to antigen-low tumor types. Specifically, I will perform a CRISPR screen to identify druggable regulators of HERV expression in human cancer cell lines. I will then validate these candidate regulators by pharmacologically targeting them and testing the induction of type-I interferon and antigenic responses in these cells. Finally, I will evaluate whether ERV-specific CAR-T cells can react to ERV-induced cells in vivo. This proposed research will clarify the mechanisms by which ERVs are epigenetically regulated in cancer, and identify novel and actionable targets for re-expressing ERVs in difficult-to-treat tumor types. This will lead to improved immunotherapeutic strategies for treating cancers with poor patient outcomes.
Immunotherapies have been revolutionary for treating a variety of cancer types, but still many patients do not respond or become resistant to currently available therapies, highlighting the need for more effective melanoma treatments. Endogenous retroelement re-expression may be a strategy for rendering tumors more immunogenic and therefore more treatable through immunotherapies, but this remains understudied. This proposal will examine the role of factors controlling expression of ERVs in augmenting the anti-tumor immune response, which will improve our understanding of cancer immunology and may identify new targets for therapeutic development.
