Role of Tspan5 in MHC I antigen presentation and cancer immune evasion

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Abstract CD8 T lymphocytes are the major mechanism by which the immune system eliminates cancers and virally infected cells. CD8 T cells detect these abnormal targets by recognizing immunogenic peptides displayed on MHC I molecules. Cancers and viruses can evade immune control by inhibiting MHC I antigen presentation, making it harder for CD8 T lymphocytes to detect and kill these pathological cells. Therefore, it is important to understand the mechanisms that regulate antigen presentation as well as the mechanisms by which tumors dysregulate these processes - this is the overall goal of this proposal. Our proposal is based on our discovery in an unbiased forward genetic screen of a Tetraspanin (Tspan5) that unexpectedly organizes MHC I molecules in ways that amplify theair ability to stimulate CD8 T cell responses. Our 1st aim will elucidate the underlying molecular mechanisms for this biological effect. This Aim will test the hypothesis that Tspan5 organizes MHC I molecules into stimulatory membrane microdomains that by virtue of size, MHC I density and/or incorporation of other key ligands markedly increases the efficiency of antigen presentation. Our 2nd aim will elucidate how, when and where Tspan5-MHC I microdomains form. This aim will test the hypotheses that peptide-MHC I complexes are incorporated into Tspan5 immunostimulatory microdomains upon release from the peptide-loading complex in the ER, through specific molecular interactions with Tspan5 and other Tspan family members, and then these immunostimulatory microdomains are trafficked to and maintained on the plasma membrane for display. Our 3rd Aim is based on our finding that certain cancers, including renal cell carcinomas, significantly downregulate Tspan 5 expression. The hypothesis underlying our 3rd Aim is that this loss of expression of Tspan5 is one of the ways that cancers escape immune surveillance and control and thereby progress. A corollary of this hypothesis is that the loss of Tspan5 is a mechanism that will influence resistance to immunotherapy; as such, Tspan5 could provide a much-needed biomarker for identifying patients who will not respond to immunotherapy and could also be a potential therapeutic target to restore responses to such therapy. Our experimental approach will use isogenic Tspan5-edited renal cell cancers (loss of function and gain of function) in preclinical models with humanized and wild type mice to define the role of Tspan5 in tumor immune evasion and responsiveness to immunotherapy with checkpoint blockade for both human and mouse tumors. Finally, we will translate these findings into human cancer patients by investigating whether Tspan5 expression is a biomarker that can predict clinical course. Our hypotheses and feasibility of the proposed experiments are supported by strong preliminary data. Taken together, our proposed experiments will go from basic mechanistic studies, which will elucidate a potentially fundamental and novel mechanism for optimizing the ability of APCs to stimulate T cell responses, to preclinical and clinical studies, which will define how loss of this mechanism affects immune control of cancers and clinical outcomes.