HLA polymorphism impacts immune response to neoepitopes and survival in APOBEC-mutated cancers

Summary APOBEC3A and APOBEC3B genome mutators, key drivers of tumor evolution and drug resistance, may also contribute to generation of neoepitopes for cytotoxic T cells (CTLs). Given the vast polymorphism of Class I HLA, the CTL immunopeptidome, comprised of all possible 8-11mer peptides presented by several thousand HLA class I alleles is highly variable in the population based on individual HLA class I genotype. We developed a genome-wide immunogenicity scanning platform to systematically explore how APOBEC3A/B-driven mutational landscapes reshape the immunogenic potential of the human immunopeptidome. We evaluated all possible APOBEC3-mediated mutations, numbering in the billions, for their potential impact on peptide:MHC and T cell receptor binding. We found that HLA class I alleles vary markedly in their immunopeptidome’s susceptibility to APOBEC3A/B-induced mutational changes, with fewer alleles exhibiting significant increase in neoepitope immunogenicity. Mutations within APOBEC3B hotspots displayed the greatest capacity for enhanced immunogenicity and neo-epitope formation. We further found that the cumulative potential of an individual’s HLA haplotype’s immunopeptidome to gain immunogenicity upon APOBEC3-mediated mutation is a robust predictor of survival in APOBEC3-mutated tumors and correlates with enhanced CD8+ T cell activation. Thus, HLA haplotype is a prognostic marker in APOBEC3-mutated tumors, offering insights into the interplay between the source of cancer genome instability and immune surveillance. Significance statement This work is the first to conduct a genome-wide scan to quantify the impact of A3A- and A3B-mediated mutations on the immunogenicity changes in the human immunopeptidome presented by several thousand HLA class I alleles. We found that the effects of APOBEC3-mediated mutations vary significantly across the immunopeptidomes of different HLA alleles, and that HLA genotype is a predictor of survival and immune activation status in APOBEC3-mutated tumors, reflecting each individual’s unique HLA class I immunopeptidome’s propensity for either increased or decreased immunogenicity when altered by A3A and/or A3B. The identification of HLA genotype as a biomarker in APOBEC3-mutated tumors presents a promising opportunity for developing personalized immunotherapy strategies and exploring potential A3 inhibition. This study highlights that the effects of APOBEC3-mediated mutations on immunogenicity are not random; rather, individual HLA class I polymorphisms determine whether these mutations enhance or suppress anti-tumor immunity, which has direct prognostic implications for solid tumors.