Antigenic cancer persister cells survive direct T cell attack

Drug-tolerant cancer persister cells were reported fifteen years ago as cells in 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 an antigenic persister state which survives weeks of cytotoxic T lymphocyte (CTL) attack. In contrast to immune evasion mechanisms that limit immune detection or activation, antigenic persisters robustly activate CTLs which deliver Granzyme B, secrete IFNγ, induce tryptophan starvation, and initiate persister cell apoptosis. However, instead of dying, persisters paradoxically leverage apoptotic stress to suppress inflammatory death and acquire mutations and epigenetic changes which enable outgrowth of CTL-resistant cells. Furthermore, persister cells undergoing sublethal apoptosis are enriched in inflamed human and mouse tumors which have regressed during immunotherapy. These findings reveal that adaptive evolution mediated by persister cells surviving direct T cell attack presents a barrier to complete immune-mediated tumor rejection. Untreated A375 melanoma cells (parental) or residual A375 melanoma cells that survived 15 days of NY-ESO-1 CTL coculture (CTL-tolerant persister cells) were analyzed using scRNAseq.