Altered HLA‐A2‐restricted TP53 epitope induces specific CTL cytotoxicity against hepatocellular carcinoma

Abstract

AbstractHigh‐frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene‐encoded protein may serve as a tumor antigen to elicit tumor‐specific immune responses. In this study, we detected widespread expression of shared TP53‐Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA‐A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53‐Y220C neoantigen to yield a TP53‐Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53‐Y220C and TP53‐Y220C (L2) neoantigens against multiple HLA‐A0201‐positive cancer cells expressing TP53‐Y220C neoantigens; however, the TP53‐Y220C (L2) neoantigen showed higher cytotoxicity than the TP53‐Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53‐Y220C (L2) neoantigen‐specific CTLs relative to TP53‐Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53‐Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers.