A pan-cancer atlas of T cell targets

T-cell-based immunotherapies have revolutionized cancer treatment, yet only a minority of patients respond to these approaches, significantly constrained by the limited knowledge of tumor-specific antigens. Here we present a comprehensive map of T cell targets across 21 cancer types, revealing actionable tumor-specific targets in 86% of tumors. To define the repertoire of actionable T cell targets, we conducted a comprehensive pan-cancer analysis integrating data from 7,473 RNA-Seq datasets, 1,564 immunopeptidomes and 208 cancer single-cell datasets, comparing these against 17,384 normal samples covering 51 tissues. Our analysis uncovered 88 viable surface protein targets and 15,079 tumor-specific HLA-presented antigens, deriving from 11 distinct molecular events, across 21 tumor types, providing a comprehensive resource for T-cell-based immunotherapy development. We highlight 128 promising new tumor targets and validate 20 targets across five antigen classes. Among the antigens uncovered, we highlight 339 previously uncharacterized neoantigens, a new PMEL splicing peptide that we expect to be a superior antigen to the clinical target, novel self-antigens, peptides derived from ORFs previously unknown to encode proteins, and novel tumor-specific microbial targets. These findings significantly expand the therapeutic landscape of T cell therapies. To catalyze therapeutic development, we have made our pan-cancer target atlas and accompanying toolkit available to the scientific community and expect these resources will pave the way for immunotherapies across multiple cancers.