Antigen-specific impairment of adoptive T-cell therapy against cancer: players, mechanisms, solutions and a hypothesis

摘要: Adoptive cell therapy (ACT) destroys tumors with infused cytotoxic T lymphocytes (CTLs). Although successful in some settings, ACT is compromised due to impaired survival or functional inactivation of the CTL. To better understand mechanisms involved, we have exploited a mouse model leukemia expressing ovalbumin as tumor neoantigen address these questions: (i) Is CTL impairment during antigen specific? (ii) If yes, which are antigen-presenting cells responsible? (iii) Can this information assist development complementary therapies improve ACT? Our results indicate that target (tumor) cells, not cross-presenting main culprits antigen-specific inactivation. We find affinity/avidity CTL-tumor interaction has little influence on outcomes, while density major determinant. Reduction burden mild non-lymphoablative and non-inflammatory chemotherapy can dramatically efficacy may minimize side-effects. propose general mechanism for anti-self same tissues where activity anti-foreign preserved, based cells. This mechanism, tentatively call stunning, evolved protect infected sites from self-destruction by inactivate