Immunoediting in Cutaneous Squamous Cell Carcinoma

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PROJECT SUMMARY: Immunosuppressed transplant recipients have a 65-253 fold higher risk of developing cutaneous squamous cell carcinoma (cSCC) and are contraindicated for treatment with immune checkpoint inhibitors, presenting an important unmet clinical need. The ability of T cells to constrain cSCC is demonstrated by the response of 32- 46% of immunocompetent patients to immune checkpoint inhibitors. However, cSCC has the potential to evade an active T cell response as demonstrated by the formation of cSCC in immunocompetent patients and resistance to immune checkpoint inhibition in some patients. Prior work suggests that evasion of an active T cell response occurs through the process of immunoediting, in which T cells destroy tumors that present mutated tumor proteins that bind the T cell receptor (neoantigens), and thus select for less immunogenic tumors. This proposal will compare the neoantigen profile and immune escape mechanisms in tumors and tumor-adjacent skin from immunosuppressed and immunocompetent individuals as a novel approach to evaluate the role of T cells in immunoediting. Evaluating the neoantigen profile in carcinogen-exposed tumor- adjacent skin will additionally provide evidence for immunoediting before the formation of a clinically apparent lesion. Furthermore, since cSCC in immunosuppressed patients develops in the context of diminished T cell function, this proposal tests the innovative concept that these patients will have a neoantigen profile that is more amenable to treatment with a personalized neoantigen vaccine. The Hastings laboratory has created an MHC class I neoantigen prioritization model with high accuracy in predicting neoantigens that elicit a T cell response, which will be applied to evaluate the neoantigen profiles of cSCC from immunosuppressed and immunocompetent individuals. The Hastings laboratory has also generated and characterized a solar- simulated light induced, transplantable cSCC tumor that will be used to test vaccine efficacy in the proposed studies. Preliminary data demonstrate that the cSCC transplantable model is constrained by T cells and vaccination with irradiated tumor cells protects from tumor challenge. This proposal will test the central hypothesis that cSCC and carcinogen-exposed, tumor-adjacent skin from immunosuppressed individuals will have a more immunogenic neoantigen profile and less frequent immune escape mechanisms compared to cSCC from immunocompetent individuals. Aim 1 of this proposal will compare the neoantigen profile and immune escape mechanisms between immunosuppressed and immunocompetent patients. Aim 2 will compare the neoantigen profile and immune escape mechanisms of cSCC from mice with and without a functional T cell repertoire and demonstrate the efficacy of cancer vaccines in immunosuppressed mice. The impact of the project is to provide evidence for neoantigen vaccines as an important treatment option for immunosuppressed patients and systematically characterize the immune escape mechanisms in cSCC to determine additional targets of therapy for cSCC in immunocompetent patients.