RESUMO
Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.
RESUMO
Major histocompatibility complex class-II-restricted presentation by nonprofessional antigen-presenting cells in the tumor microenvironment can regulate antitumor T-cell responses. In murine models, tumor cell-specific MHC class II expression decreases in vivo tumor growth, dependent on T cells. Tumor cell-specific MHC class II expression is associated with improved survival and response to immune checkpoint inhibitors in human cancers. Antigen-presenting cancer-associated fibroblasts (apCAF) present MHC class-II-restricted antigens and activate CD4 T cells. The role of MHC class II on apCAFs depends on the cell of origin. MHC class II on tumoral lymphatic endothelial cells leads to expansion of regulatory T cells and increased in vivo tumor growth.
