Level of Expression of MHCI-Presented Neoepitopes Influences Tumor Rejection by Neoantigen-Specific CD8⁺ T Cells

Neoantigen-targeted therapy holds an array of benefits for cancer immunotherapy, but the identification of peptide targets with tumor rejection capacity remains a limitation. To better define the criteria dictating tumor rejection potential, we examined the capacity of high-magnitude T-cell responses induced toward several distinct neoantigen targets to regress MC38 tumors. Despite their demonstrated immunogenicity, vaccine-induced T-cell responses were unable to regress established MC38 tumors or prevent tumor engraftment in a prophylactic setting. Although unable to kill tumor cells, T cells showed robust killing capacity toward neoantigen peptide–loaded cells. Tumor-cell killing was rescued by saturation of target peptide–loaded MHCs on the cell surface. Overall, this study demonstrates a pivotal role for target protein expression levels in modulating the tumor rejection capacity of neoantigens. Thus, inclusion of this metric, in addition to immunogenicity analysis, may benefit antigen prediction techniques to ensure the full antitumor effect of cancer vaccines.