Antigenic cancer persister cells survive direct T cell attack

Drug-tolerant persister cancer cells were first reported fifteen years ago as a quiescent, reversible cell state which tolerates unattenuated cytotoxic drug stress. It remains unknown whether a similar phenomenon contributes to immune evasion. Here we report a persister state which survives weeks of direct cytotoxic T lymphocyte (CTL) attack. In contrast to previously known immune evasion mechanisms that avoid immune attack, antigenic persister cells robustly activate CTLs which deliver Granzyme B, secrete IFNγ, and induce tryptophan starvation resulting in apoptosis initiation. Instead of dying, persister cells paradoxically leverage apoptotic caspase activity to avoid inflammatory death. Furthermore, persister cells acquire mutations and epigenetic changes which enable outgrowth of CTL-resistant cells. Persister cell features are enriched in inflamed tumors which regressed during immunotherapy in vivo and in surgically resected human melanoma tissue under immune stress ex vivo. These findings reveal a persister cell state which is a barrier to immune-mediated tumor clearance.