Class II-restricted tumor neoantigens are required for the production of functional cytolytic CD8 T cells and response to checkpoint blockade therapy Elise Alspach1, Danielle M. Lussier1, Matthew M. Gubin1, Cora D. Arthur1 and Robert D. Schreiber1 1Department of Pathology and Immunology, Washington University School of Medicine
Whereas the roles of CD8+ T cells in the anti-tumor response have been a major focus of current tumor immunology research, the roles that CD4+ T cells play in the response have received much less attention. Additionally, while we and others have established pipelines for the prediction of MHC class I-restricted neoantigens expressed in tumors, much less is known about the nature of the neoantigens that are targets for CD4+ T cell responses. Given our success in identifying the class I-restricted neoantigens mLama4 and mAlg8 from the T3 MCA-induced sarcoma line, we sought to develop and validate a comparably useful pipeline for class II-restricted neoantigens in T3 and characterize their role in controlling tumor outgrowth. Using a novel bioinformatics approach that is based on MHC class II binding prediction algorithms and antigen abundance, we identified a N711Y mutation in the integrin Itgb1 that is the major CD4+ T cell neoantigen in T3. Enforced expression of either mLama4 or mItgb1 failed to render a non-antigenic sarcoma cell line (KP9025) sufficiently immunogenic to be rejected in tumor bearing mice treated with either control monoclonal antibody (mAb) or immune checkpoint blocking (ICB) mAbs. In contrast, KP9025 expressing both mLama4 and mItgb1 were spontaneously rejected in a subset of mice treated with control mAb, and the tumors were rejected in mice treated therapeutically with anti-PD-1 and anti-CTLA-4 either alone or in combination. We found that the presence of mItgb1 in KP9025 tumors resulted in induction of higher percentages and greater numbers of mLama4-specific CD8+ CTL. To test the therapeutic relevance of this observation, we vaccinated mice bearing T3 tumors with mLama4 or mItgb1 alone or a vaccine that employed a combination of mLama4 and mItgb1. We observed superior therapeutic efficacy when mice were vaccinated with both class I and class II-restricted neoantigens. These results not only document our ability to identify tumor-specific neoantigens that induce helper CD4+ T cell responses but also demonstrate the necessity of CD4+ T cell help in generating functional CD8+ CTL responses in tumor-bearing mice that respond to immune checkpoint blockade therapy.
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