Overview
- A multi-center analysis of nearly 9,300 cancer genomes found that most tumors are dominated by one of five amino acid substitution signatures.
- These protein-level mutation patterns determine the quality of neoantigens, creating tumors that are either readily recognized or effectively hidden from T cells.
- A signature associated with DNA repair defects and chemical exposures correlates with weak responses to immune checkpoint inhibitors even when tumor mutational burden is high.
- Host genetics can modify tumor visibility, with certain HLA class I variants—such as HLA-B07:02—better presenting specific mutated peptides to T cells.
- Published in Molecular Systems Biology, the work supports integrating substitution signatures with patient HLA genotypes to refine immunotherapy selection, with clinical validation still needed.