Dixon et al. highlighted the immunosuppressive role of TIM-3 in DCs and demonstrated that TIM-3 blockade promoted inflammasome activation and antitumor immunity. TIM-3 deletion in DCs, but not on CD4+ and CD8+ T cells, reduced tumor growth in mice bearing MC38-OVAdim tumors, promoted maintenance of stem-like CD8+ T cells, and increased antigen-specific CD8+ T cells with higher levels of effector cytokines. Loss of TIM-3 in migratory DCs increased inflammasome- and oxidative stress-associated gene signatures, and treatment with antioxidant or anti-IL-1β/IL-18 abolished the protective antitumor immunity of TIM-3-deleted DCs.
Contributed by Shishir Pant
ABSTRACT: T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-_ producing T cells(1), is emerging as an important immune-checkpoint molecule, with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8(+) T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs-but not on CD4(+) or CD8(+) T cells-promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8(+) effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1_ (IL-1_) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation.
Author Info: (1) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Harvard Medical Sc
Author Info: (1) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (4) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Celsius Therapeutics, Cambridge, MA, USA. (5) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. (6) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Genentech, South San Francisco, CA, USA. (9) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA, USA. Howard Hughes Medical Institute, Cambridge, MA, USA. Genentech, South San Francisco, CA, USA. (10) Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. vkuchroo@evergrande.hms.harvard.edu. Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. vkuchroo@evergrande.hms.harvard.edu. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. vkuchroo@evergrande.hms.harvard.edu.
