Cancer incognito.

Remember our musing on somatic positive selection? A recent Nature article demonstrates a fascinating take on how this process contributes to tumor cells evading the immune system (and our most novel immunotherapeutic approaches). CRISPR gene-editing enabled the authors to screen >100K unique melanoma genes to systematically assess each one’s effect on T-cell responses in vitro. The genes most responsible for immune evasion were, not surprisingly, key players in antigen presentation and interferon-gamma signaling. They then ascertained if these genes correlated with poor clinical immunotherapy responses among >11K real patient tumors within the Cancer Genome Atlas. Why is this so cool? They identify for the first time several genes which may one day serve as novel adjunct targeting pathways. This most promising: the APLNR gene noted to modulate interactions between interferon-gamma and the JAK-STAT pathway. Only time will tell if these ideas evolve into clinical efficacy, but this thoughtful drug development has us JAK-ed up.