Immunogenic potential of neopeptides depends on parent protein subcellular location

Antigen presentation via the major histocompatibility complex (MHC) is essential for anti-tumor immunity, however the rules that determine what tumor-derived peptides will be immunogenic are still incompletely understood. Here we investigate whether protein subcellular location driven constraints on accessibility of peptides to the MHC associate with potential for peptide immunogenicity. Analyzing over 380,000 peptides from studies of MHC presentation and peptide immunogenicity, we find clear spatial biases in both eluted and immunogenic peptides. We find that including parent protein location improves prediction of peptide immunogenicity in multiple datasets. In human immunotherapy cohorts, location was associated with response to a neoantigen vaccine, and immune checkpoint blockade responders generally had a higher burden of neopeptides from accessible locations. We conclude that protein subcellular location adds important information for optimizing immunotherapies. HighlightsO_LIPeptides eluted from class I and II MHC reflect biases in the subcellular location of the parent proteins C_LIO_LIAn embedding-based indicator of parent protein location improves prediction of neoepitope immunogenicity and immunotherapy response C_LIO_LINeoepitope location improves estimation of effective neoantigen burden and stratification of potential for immunotherapy response C_LI