TIM-3 restrains anti-tumour immunity by regulating inflammasome activation

Karen O. Dixon, Marcin Tabaka, Markus A. Schramm, Sheng Xiao, Ruihan Tang, Danielle Dionne, Ana. C. Anderson, Orit Rozenblatt-Rosen, Aviv Regev and Vijay K. Kuchroo ()
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Karen O. Dixon: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital
Marcin Tabaka: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Markus A. Schramm: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital
Sheng Xiao: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital
Ruihan Tang: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital
Danielle Dionne: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Ana. C. Anderson: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital
Orit Rozenblatt-Rosen: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Aviv Regev: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Vijay K. Kuchroo: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital

Nature, 2021, vol. 595, issue 7865, 101-106

Abstract: Abstract T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells1, 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-1β (IL-1β) 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.

Date: 2021
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DOI: 10.1038/s41586-021-03626-9

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