title: Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors.
abstract: Strategies to activate and rescue exhausted tumor-specific T cells, including the use of monoclonal antibodies (mAb) that block the negative costimulatory receptors CTLA-4 and PD-1 are proving very effective, but TIM3 has been relatively neglected as a target. Here we report an extensive characterization of the therapeutic activity and mechanism of action of an anti-mouse TIM3 mAb against experimental and carcinogen-induced tumors. For the first time we specifically define the mechanism of antitumor action of anti-TIM3 requiring IFN-γ producing CD8(+) T cells and CD4(+) T cells, and a higher ratio of tumor infiltrating CD8(+):CD4(+) T cells correlating with therapeutic success. Interestingly, in some models, anti-TIM3 appeared to be effective sometime before the appearance and accumulation of significant TIM3(+)PD-1(+) T cell populations in tumor bearing mice. Anti-TIM3 displayed modest prophylactic and therapeutic activity against a small fraction of carcinogen-induced sarcomas, but comparative and combination studies of anti-TIM3 with anti-CTLA-4 and anti-PD-1 against experimental and carcinogen-induced tumors suggested that these agents might be well-tolerated and very effective in combination.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Shin Foong
authors.initials: SF
authors.lastname: Ngiow
authors.forename: Bianca
authors.initials: B
authors.lastname: von Scheidt
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D060908:CTLA-4 Antigen; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000737:chemistry*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C448908:HAVCR2 protein, human; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; D007371:Interferon-gamma