Lack of detectable neoantigen depletion signals in the untreated cancer genome

Somatic mutations can result in the formation of neoantigens, immunogenic peptides that are presented on the tumor cell surface by HLA molecules. These mutations are expected to be under negative selection pressure, but the extent of the resulting neoantigen depletion remains unclear. On the basis of HLA affinity predictions, we annotated the human genome for its translatability to HLA binding peptides and screened for reduced single nucleotide substitution rates in large genomic data sets from untreated cancers. Apparent neoantigen depletion signals become negligible when taking into consideration trinucleotide-based mutational signatures, owing to lack of power or to efficient immune evasion mechanisms that are active early during tumor evolution. Pan-cancer genomic analyses based on HLA affinity predictions show that apparent neoantigen depletion signals in untreated tumors become negligible after correction for trinucleotide-based mutational signatures.