TIM3 Blockade in Dendritic Cells May Potentiate Antitumor Immunity

T-cell immunoglobulin and mucin-containing molecule 3 (TIM3) is implicated as an immune checkpoint molecule and is expressed on several different types of immune cells. However, exactly how therapeutic blockade of TIM3 might influence antitumor immunity is currently unknown. Using single-cell RNA sequencing and mouse models, Dixon, Tabaka, and colleagues demonstrated that loss of TIM3 on dendritic cells (DC), but not on T cells, promotes an antitumor immune response. Conditional knockout mice lacking TIM3 in CD8⁺ T cells, both CD8⁺ and CD4⁺ T cells, or T regulatory cells had no change in the tumor burden of engrafted murine colon cancer cells. Single-cell RNA sequencing and flow cytometry analysis of cells from wild-type mice with colon tumors revealed the highest expression of TIM3 on DCs, as well as high expression on intratumoral monocytes and macrophages. Targeted deletion of TIM3 in DCs resulted in a reduction in tumor burden in mice engrafted with colon cancer, lung cancer, or melanoma cells. Subcutaneous engraftment of colon cancer cells into mice with conditional loss of TIM3 prevented DCs from expressing a regulatory program and increased the number of PD-1⁺ tumor-infiltrating lymphocytes (TIL) found in tumors. Analysis of TILs showed an increased number of stem-like CD8⁺ cells, memory precursor T cells, and cells entering the effector lineage, together indicating promotion of a protective immune response in tumors from mice where TIM3 expression on DCs is lost. Further single-cell RNA-sequencing analysis of DCs lacking TIM3 from murine tumors showed promotion of DC functionality and enhancement of antigen-specific antitumor immunity. Finally, TIM3 deletion in DCs resulted in accumulation of reactive oxygen species, activating the NLRP3 inflammasome. Blocking inflammasome activation either directly or via inhibition of downstream effector cytokines IL1β and IL18 reversed the antitumor effects of deletion of TIM3. These results highlight the potential of TIM3 blockade to harness inflammasome activity to boost antitumor immunity.

Dixon KO, Tabaka M, Schramm MA, Xiao S, Tang R, Dionne D, et al. TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature 2021;595:101–6.

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