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Impact of HLA Aberrations on Tumor Neoepitope Presentation

TP53 mutations may encode tumor-specific truncal neoantigens for targeting cytotoxic T lymphocyte (CTL). Using mass spectrometry followed by X-ray crystallographic analysis of HLA-bound p53 neoantigens, clinical tumor database analyses, and functional studies of neoantigen-directed T cell receptors (TCRs), we have built a comprehensive p53 immunopeptidome. As a component of this study, we noted that tumors with neoantigens displayable on HLA-A*02:01 or HLA-B*07:02, and structurally divergent from p53 wild-type peptide-HLA complexes, may exploit an allele's absence for growth in patients. The data deposited highlights that in brain metastasis of an ovarian cancer, that a damaged HLA-A*02:01 allele resulted in inability to present the p53 I195F neoepitope (GLAPPQHLFRV). Conversely, a simultaneously processed glioblastoma sample, sequenced as a control (and bearing a p53 R248W mutation on an A*24:02/A*32:01 background), revealed full exome genomic reads and transcript reads of the HLA-A locus. This indicated that biallelic HLA-A loss in the 10-417-1023 tumor was not a technical issue but represented damage to the 5' encoding exons of HLA-A.