Abstract 1922: Protective tumor neo-epitopes are processed from conformationally stable neo-antigen segments

Abstract

Abstract Immunogenic tumor neo-epitopes are the basis of successful checkpoint immunotherapy for cancer, and they potentially offer a target for personalized cancer vaccines. However, the frequency of immunologically protective neo-epitopes appears to be very low in comparison to the frequency of tumor mutations. Vaccine designers typically select neo-epitopes by demonstrable gene expression and elevated MHC class I binding, anticipating that corresponding CD8+ T cells will be protective; but CD4+ T-cells are more often correlated with therapeutic effects. CD4+ T cells are most well known for helping B cells make antibodies, and B cells also have recently been implicated in protection from tumors. Antigen-presenting cells, including dendritic cells, B cells, and macrophages present epitope peptides in complexes with class II MHC molecules (MHCII) to CD4+ T cells, and CD4+ T cells signal responding cells to eliminate tumor cells. Studies on immunodominant CD4+ T-cell epitopes from foreign antigens suggest that immunogenicity depends on antigen conformational stability. Likewise, the immunogenic CD4+ neo-epitopes of tumors could be associated with mutations affecting residues in conformationally stable protein segments. In order to test this hypothesis, we surveyed existing tumor neo-epitope data to analyze the conformational context of neo-epitopes that are associated with protection from tumors. First, protective neo-epitopes are three-fold more likely to occur in a crystal structure (67%) than other potential neo-epitopes (22%). Second, the protective neo-epitopes are enriched within or adjacent to conformationally stable segments of the neo-antigens, as reported by the Antigen Processing Likelihood algorithm. Third, the distribution of mutations between functionally similar hotspots encoding R248 and R273 in the gene for the p53 tumor suppressor is consistent with increased immunologic selection in tumors subjected to increased immune response. These results suggest that neo-epitope evaluation for cancer prognosis and vaccines should include the analysis of conformational stability in the neo-antigen. Citation Format: Samuel J. Landry. Protective tumor neo-epitopes are processed from conformationally stable neo-antigen segments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1922.