Abstract
The incidence of recurrent oncogenic alterations in a tumor is influenced by the MHC I genotype.
Major finding: The incidence of recurrent oncogenic alterations in a tumor is influenced by the MHC I genotype.
Approach: Binding affinity-based presentation scores were calculated for the pan-cancer MHC I peptidome.
Impact: MHC I genotypes may stratify patients for therapy and preventive care.
The ability of lymphocytes to recognize tumor neoantigens is mainly dependent upon the binding affinity of surface MHC I for peptides and is critical for cancer immunotherapy efficacy. Recently, studies have focused upon increasing the immunogenicity of tumors to counter cancer immunosuppression, but less is known about the impact of the immune system on the tumor genome during the early stages of tumorigenesis. To elucidate the role of patient-specific MHC I landscapes on mutation-derived neoantigens, Marty and colleagues developed an algorithm to calculate an MHC I peptide binding affinity–based presentation score as a predictor of the antigenicity of oncogenic alterations and to evaluate the tumor MHC I genotype. Patient-specific scores, generated by the aggregation of the top binding affinity score for a residue across all 6 MHC alleles and termed Patient Harmonic-mean Best Rank (PHBR) scores, were calculated for 9,176 patients in The Cancer Genome Atlas (TCGA). Integrated analysis of the resulting patient MHC I genotypes and patient mutation status revealed that the PHBR score was predictive for identifying recurrent oncogenic driver alterations in patients, but not for passenger mutations and germline variants, suggesting that the presentation of driver alterations occurs early during cancer immunoediting. Interrogation of TCGA patients as a population and not individually identified a significant correlation between the PHBR score across patients and the frequency of mutations among tumors. Comparison of the PHBR for the native and mutated residues revealed that native residues were slightly more poorly presented than mutated residues, and that native and mutated residues associated with oncogenic alterations were significantly more poorly presented compared with native and mutated residues associated with randomly generated mutations. These results describe the role of the patient MHC I genotype during early tumor development by selecting which oncogenic driver mutations are more likely to endure immune action in an individual and suggest MHC I genotype-based strategies to predict patient cancer susceptibilities.
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