Making invisible cancers visible: A new route to turn 'cold' tumors 'hot'

This study reveals how certain tumors, known as "cold" tumors, are able to hide their cancer-causing mutations from T cells, making them difficult to target with immunotherapy. Researchers from Dana-Farber Cancer Institute have discovered that mutations in the p53 tumor-suppressor protein, which occurs in about half of all human cancers, can render these mutations invisible to T cells.

This is because p53 mutations may fail to display useful molecular targets on the tumor cell surface, which T cells rely on for identification. The study found that many p53 hotspot mutations occur in regions that are poorly processed and do not generate detectable surface targets. Additionally, some tumors lack the necessary HLA molecules to display immunogenic p53 fragments.

The researchers identified several potential solutions to this problem, such as inhibiting the enzyme ERAP1 or blocking it with an inhibitor, which could restore recognition of cancer cells by p53-specific T cells. Another challenge arises with common p53 R175H mutation, where the mutant p53 fragment binds to its HLA molecule too weakly, resulting in a short-lived complex that is difficult for the immune system to recognize.

The researchers suggest that drugs that alter the immunopeptidome, making cancer cells display new peptide targets, could be a valuable approach. By converting an "immunologically inconspicuous" tumor into one that is more visible to the immune system, these drugs could potentially turn a "cold" tumor "hot" and make it more susceptible to immunotherapy.