Antigenic cancer persister cells survive direct T cell attack

Cancer persister cells survive cytotoxic drug stress through nongenetic mechanisms, but it is unclear whether cancer cells enter a similar survival state during immunotherapy. Using a long-term coculture model of human melanoma cells with antigen-specific CTLs, we found that antigenic cancer cells can enter a persister state in response to CTL attack and survive despite delivery of granzyme B, mitochondrial outer membrane permeabilization, and apoptotic caspase activation. Although both CTL- and drug-tolerant persister cells undergo sublethal apoptosis, they differ markedly in their transcriptomes, pro- and anti-apoptotic factors, and vulnerabilities, including opposite ferroptosis sensitivities. CTL-tolerant persister cells occupy a caspase-inhibited state partially dependent on inhibitor of apoptosis proteins, yet exhibit multiple stress-dependent features including DNA damage and mutagenesis, and are growth-arrested as a result of IFNgamma-IDO1-mediated tryptophan starvation. Apoptotic caspase activity protects CTL-tolerant persister cells from potent caspase-independent death and suppresses type I IFN production. Persister cell features are enriched in inflamed tumors that regressed during immunotherapy in vivo and in surgically resected human melanoma ex vivo. These findings reveal a sublethal apoptotic persister state that allows cancer cells to survive CTL attack and identify a targetable barrier to durable immunotherapy responses.