Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy

PROJECT SUMMARY 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.