Composite impact of genome-wide APOBEC3-mediated mutations and HLA haplotype on cancer immunogenicity has a sex-biased survival impact

APOBEC3A and APOBEC3B genome mutator enzymes drive tumor evolution and drug resistance. However, their mutational activity can also generate neoepitopes that activate cytotoxic T cells (CTLs). Given the high polymorphism of Class I HLA, the CTL immunopeptidome is individual-specific. We used a genome-wide immunogenicity scanning pipeline to assess how APOBEC3A/B-induced mutations affect the immunogenicity of the entire human immunopeptidome, consisting of all possible 8-11mer peptides restricted by several thousand HLA class I alleles. We evaluated several billion APOBEC3-mediated mutations for their potential to alter peptide:MHC and T cell receptor binding, either increasing or decreasing immunogenicity. We then ranked HLA alleles based on the degree to which their restricted immunopeptidome lost or gained immunogenicity when mutated by APOBEC3A or APOBEC3B. We found that HLA class I alleles vary infinitely in the proportions of their immunopeptidome whose immunogenicity is diminished vs. enhanced by APOBEC3-mediated mutations, with mutations in APOBEC3B hotspots having the greatest potential for enhancement of immunogenicity. The cumulative potential of an individual’s HLA haplotype’s immunopeptidome to gain or lose immunogenicity upon APOBEC3-mediated mutation predicts survival in APOBEC3-mutated tumors and correlates with increased CD8+ T cell activation. Thus, HLA haplotype is a prognostic marker in APOBEC3-mutated tumors.