The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 6; pp. 1154 - 1167.e7
• Main Authors: de Mingo Pulido, Álvaro, Hänggi, Kay, Celias, Daiana P., Gardner, Alycia, Li, Jie, Batista-Bittencourt, Bruna, Mohamed, Eslam, Trillo-Tinoco, Jimena, Osunmakinde, Olabisi, Peña, Reymi, Onimus, Alexis, Kaisho, Tsuneyasu, Kaufmann, Johanna, McEachern, Kristen, Soliman, Hatem, Luca, Vincent C., Rodriguez, Paulo C., Yu, Xiaoqing, Ruffell, Brian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2021; Elsevier Limited
• Subjects: Animals; Antibodies; Biological Transport - physiology; Cancer; Cancer immunotherapy; CD103+ cDC1; Cell Line; Cell Line, Tumor; Cell surface; cGAS; Chemokines; Chemokines - metabolism; Chemotherapy; Clinical trials; Clustering; Combinatorial analysis; CXCL10; CXCL9; Cytoplasm - metabolism; Dendritic cells; Dendritic Cells - metabolism; Deoxyribonucleic acid; DNA; DNA - metabolism; Endocytosis; Endocytosis - physiology; Female; Galectin-9; Gene expression; Genes; HEK293 Cells; Hepatitis A Virus Cellular Receptor 2 - metabolism; HMGB1 protein; Humans; Immunoglobulins; Immunotherapy; Immunotherapy - methods; Interferon; Ligands; Localization; Lymphocytes; Mammary gland; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Nucleotidyltransferases - metabolism; Paclitaxel; Peripheral blood; Receptors; Signal Transduction - physiology; Spleen; STING; TIM-3; Tumors; type I interferon; XCR1+ cDC1; type I interferon; CXCL10; CXCL9; dendritic cells; XCR1+ cDC1; DNA; cGAS; STING; CD103+ cDC1; TIM-3; CD103(+) cDC1; XCR1(+) cDC1
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.04.019

Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1+ classical dendritic cells (cDC1), thereby limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting. TIM-3 blockade increased uptake of extracellular DNA by cDC1 through an endocytic process that resulted in cytoplasmic localization. DNA uptake and efficacy of TIM-3 blockade required DNA binding by HMGB1, while galectin-9-induced cell surface clustering of TIM-3 was necessary for its suppressive function. Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy. [Display omitted] •TIM-3 blockade promotes endocytosis of extracellular DNA by dendritic cells•DNA uptake and CXCL9 expression by dendritic cells is HMGB1 dependent•Galectin-9 regulates TIM-3 cell surface clustering and inhibitory function•Antitumor efficacy of TIM-3 mAb and paclitaxel is dependent upon cGAS and STING Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. de Mingo Pulido et al. provide insight into the underlying mechanisms by revealing that TIM-3 suppresses HMGB1-dependent endocytosis of extracellular DNA and the subsequent activation of the cGAS-STING pathway in intra-tumoral dendritic cells.