Antigen-specific impairment of adoptive T-cell therapy against cancer: players, mechanisms, solutions and a hypothesis.
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 the mechanisms involved, we have exploited a mouse model of leukemia expressing ovalbumin as a tumor neoantigen to address these questions: (i) Is CTL impairment during ACT antigen specific? (ii) If yes, which are the antigen-presenting cells responsible? (iii) Can this information assist the development of complementary therapies to improve ACT? Our results indicate that the target (tumor) cells, not cross-presenting cells, are the main culprits of antigen-specific CTL inactivation. We find that the affinity/avidity of the CTL-tumor cell interaction has little influence on ACT outcomes, while tumor density is a major determinant. Reduction of tumor burden with mild non-lymphoablative and non-inflammatory chemotherapy can dramatically improve the efficacy of ACT and may minimize side-effects. We propose a general mechanism for the inactivation of anti-self CTL in the same tissues where the activity of anti-foreign CTL is preserved, based on the density of target cells. This mechanism, which we tentatively call stunning, may have evolved to protect infected sites from self-destruction and is exploited by tumors to inactivate CTL.
Department of Microbiology and Immunology, Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, Vic., Australia.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Vic., Australia.
Jose A
JA
Villadangos
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015551:Autoimmunity; D019496:Cancer Vaccines / Q000276:immunology*; D002470:Cell Survival; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D047368:Tumor Burden
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines
antigen presentation; cancer; cytotoxic T cells; dendritic cells; immunotherapy; myeloid-derived suppressor cells