651 Melanoma persister cells survive CD8 T cell attack and seed acquired resistance to immunotherapy

Clinical data indicate that acquired resistance occurs in nearly half of cancer patients who initially respond to immunotherapy. The molecular processes by which immunotherapy sensitive tumors survive and acquire are poorly understood. For targeted therapy chemotherapy, is thought involve the survival quiescent “persister” cells form a reservoir can seed tumor regrowth. immunotherapy, little known about effective We hypothesize melanoma persister cell population survives direct CD8 T attack seeds subsequent relapse. To explore this question, we have developed models primary human transduced with retrovirus expressing antigen-specific receptor (TCR cells) cocultured endogenously present cognate antigens. focus on setting, expose continually refreshed TCR for 12 or more days after death largely ceases residual surviving remain. Upon removal, regrow but become resensitized retreatment cells. This reversibility tolerance indicates nonmutational mechanism. further extended coculture (> 1 month), minority into proliferating colonies irreversibly resistant also observe similar formation regrowth upon treatment purified cytokines IFNgamma TNFalpha indicating “bystander” may distal from sites attack. Together, these findings reveal tolerate contribute