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.