Microenvironment and Immunology Anti-TIM3 Antibody Promotes T Cell IFN-g–Mediated Antitumor Immunity and Suppresses Established Tumors

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 TIM3mAb against experimental and carcinogen-induced tumors. For the first time we specifically define the mechanism of antitumor action of anti-TIM3 requiring IFN-g producing CD8þ T cells and CD4þ T cells, and a higher ratio of tumor infiltrating CD8þ:CD4þ T cells correlating with therapeutic success. Interestingly, in some models, anti-TIM3 appeared to be effective sometime before the appearance and accumulation of significant TIM3þPD-1þ T cell populations in tumor bearing mice. Anti-TIM3 displayedmodest 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. Cancer Res; 71(10); 3540–51. 2011 AACR.