How p53 mutations evade immune detection and block immunotherapy

Dana-Farber Cancer Institute research reveals how cancers with p53 mutations hide these targets from T cells, explaining why immunotherapy fails against many "cold" tumors. The study suggests altering tumor surface displays to make cancers visible to the immune system. Published in Immunity, researchers found p53 peptides are far less visible than DNA predictions suggest, with only five of 175 candidates robustly detected. Tumors also lacked necessary HLA molecules, while the ERAP1 enzyme destroyed immunogenic fragments. The p53 R175H mutation produced unstable, short-lived targets that weakened T-cell responses. The proposed "immunopeptidome shift" strategy uses drugs like ERAP1 inhibitors to expose new peptide targets, potentially converting cold tumors hot. This approach could complement existing therapies, though no drug has yet been tested in patients. The findings caution against assuming predicted mutations are useful immune targets.