Non-canonical translation of oncogenes in tumor cells generates a new class of shared and immunogenic neoepitopes for cancer immunotherapy

Cancer cells rely on alternative modes of translation for protein synthesis, promoting internal ribosome entry site (IRES)-dependent translation of mRNA subsets encoding pro-oncogenic factors. Furthermore, ribosomes translate mRNA with lower fidelity in tumor cells. Our bioinformatics analyses highlighted large numbers of non-canonical peptides specific to cancer cells derived from aberrant translation of IRES-containing oncogene mRNAs. Interestingly, these peptides contain multiple shared neoepitope candidates. To provide a complete proof-of-concept, we selected one HLA-A2 epitope candidate (LLL) derived from c-MYC , which was confirmed to be immunogenic and expressed selectively on tumor cells by targeted immunopeptidomics. This peptide is generated by a (+ 1) ribosomal frameshift of c-MYC mRNA occurring during the oncogenic transformation. TCR-engineered T cells specific to LLL epitope selectively recognized and killed tumor cells, confirming the therapeutic potential of targeting this neoepitope. Altogether, these results validate a new class of actionable shared neoepitopes derived from non-canonical translation of oncogenes.