PROJECT SUMMARY:Immunosuppressed transplant recipients have a 65-253 fold higher risk of developing cutaneous squamouscell carcinoma (cSCC) and are contraindicated for treatment with immune checkpoint inhibitors presenting animportant 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 evadean active T cell response as demonstrated by the formation of cSCC in immunocompetent patients andresistance to immune checkpoint inhibition in some patients. Prior work suggests that evasion of an active Tcell response occurs through the process of immunoediting in which T cells destroy tumors that presentmutated tumor proteins that bind the T cell receptor (neoantigens) and thus select for less immunogenictumors. This proposal will compare the neoantigen profile and immune escape mechanisms in tumors andtumor-adjacent skin from immunosuppressed and immunocompetent individuals as a novel approach toevaluate 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 apparentlesion. Furthermore since cSCC in immunosuppressed patients develops in the context of diminished T cellfunction this proposal tests the innovative concept that these patients will have a neoantigen profile that ismore amenable to treatment with a personalized neoantigen vaccine. The Hastings laboratory has created anMHC class I neoantigen prioritization model with high accuracy in predicting neoantigens that elicit a T cellresponse which will be applied to evaluate the neoantigen profiles of cSCC from immunosuppressed andimmunocompetent 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 proposedstudies. Preliminary data demonstrate that the cSCC transplantable model is constrained by T cells andvaccination with irradiated tumor cells protects from tumor challenge. This proposal will test the centralhypothesis that cSCC and carcinogen-exposed tumor-adjacent skin from immunosuppressed individuals willhave a more immunogenic neoantigen profile and less frequent immune escape mechanisms compared tocSCC from immunocompetent individuals. Aim 1 of this proposal will compare the neoantigen profile andimmune escape mechanisms between immunosuppressed and immunocompetent patients. Aim 2 willcompare the neoantigen profile and immune escape mechanisms of cSCC from mice with and without afunctional T cell repertoire and demonstrate the efficacy of cancer vaccines in immunosuppressed mice. Theimpact of the project is to provide evidence for neoantigen vaccines as an important treatment option forimmunosuppressed patients and systematically characterize the immune escape mechanisms in cSCC todetermine additional targets of therapy for cSCC in immunocompetent patients.