MHC-I Genotype Restricts the Oncogenic Mutational Landscape

Abstract

SUMMARY MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations. We found that patient MHC-I genotype-based scores could predict which mutations were more likely to emerge in their tumor. Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors. These results support that MHC-I genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors and paves the way for predicting personal cancer susceptibilities from knowledge of MHC-I genotype.

Evolutionary Pressure against MHC Class II Binding Cancer Mutations

“…This formulation of the PHBR-II score out-performed another scoring variation where peptides of varying lengths were considered (Figure S1). Two reasons contribute to the reduced performance relative to MHC-I (ROC AUC 0.75) (Marty et al, 2017). First, predicting single allele MHC-II binding has higher error than predicting single allele MHC-I binding (Andreatta et al, 2018; Paul et al, 2015; Wang et al, 2008).…”

“…This information is central to efforts to understand the role of the MHC in cancer evolution. To this end, we recently reported that MHC-I molecules play a significant role in shaping the mutational landscape of cancer (Marty et al, 2017). We demonstrated that mutations were more likely to be observed in tumors if the background MHC-I genotype resulted in poor affinity for peptides harboring the mutation, with implications for individual mutation probability and population mutation frequencies.…”

Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma

“…In contrast, driver mutations are actively selected, and expressed clonally and homogenously in cancers from many patients. Unfortunately, there have been very few driver mutations described as eliciting T cell responses, perhaps as a consequence of selection based on HLA genotype (13).…”

MHC-I genotype drives early immune selection of oncogenic mutations

“…Thus, we hypothesized that patient-specific MHC-I variation would create individual differences in which cancer-causing mutations would be undetectable by the immune system and thus would drive tumorigenesis to clinically diagnosed disease. 5 To systematically evaluate this hypothesis, we established a score representing a patient's ability to expose a mutation on the cell surface for recognition by the immune system. Existing tools rank peptides based on their binding affinity to a single MHC-I allele.…”

“…6 We developed a Patient Harmonic-mean Best Rank (PHBR) score from ranked peptide binding affinities that accounts for the contribution of a patient's six MHC-I alleles and all possible peptides containing a specific residue, and validated it against mass spectrometry data for MHC-I alleles complexed with peptides. 5 Higher PHBR scores are interpreted as poorer MHC-I presentation and lower PHBR scores are interpreted as better MHC-I presentation.…”