Identification of splice variant derived neo-antigens in head and neck squamous cell carcinoma as targets for tumor vaccine therapy

Title: Identification of splice variant derived neo-antigens in head and neck squamous cell carcinoma as targets for tumor vaccine therapy Abstract Immune checkpoint inhibitors (ICI) were recently FDA approved for first line treatment of recurrent and metastatic head and neck squamous cell carcinoma (HNSCC). However, response rates to ICI in HNSCC are less than 20%. Tumor specific neoantigens predict response to ICI therapy, and these immunogenic neoantigens represent ideal targets for vaccines to enhance ICI response. Alternative splicing events, which are present and functionally active in HNSCC, represent an understudied source of tumor-specific protein diversity and novel neoantigens. The goal of this work is to identify the potential for splice variant derived neoantigens to elicit an immune response and serve as targets for tumor vaccine development. Using an established computational pipeline, splice variant derived peptides will be predicted and prioritized. Then an immunocompetent murine model of oral cancer will be utilized to evaluate the functional immunogenicity of aberrant splicing variants. Splicing variant products that are able to elicit an immune response will then be incorporated into a vaccine and evaluated for the ability to enhance response of oral cancer to immune checkpoint inhibitors. Finally, immune response to splice variant derived human neoantigens will be evaluated in oral cancer patients to establish the role for translation of such therapies to the clinic. The proposed work has the potential to transform the landscape of tumor neoantigens in HNSCC to include previously unrecognized splicing variants derived neoantigens. These splice variants occur at a higher prevalence than somatic mutations, generate highly immunogenic protein products with more extensive sequence alteration than mutations, and their derivative neoantigens represent ideal targets for tumor vaccine development. While this work is focused in oral cancer, the role of splice variants on anti-tumor immunity can be expanded to impact other heterogeneous solid tumors.