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

Abstract

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.

• Authors: Álvaro de Mingo Pulido, Kay Hänggi, Daiana P Celias, Alycia Gardner, Jie Li, Bruna Batista-Bittencourt, Eslam Mohamed, Jimena Trillo-Tinoco, Olabisi Osunmakinde, Reymi Peña, Alexis Onimus, Tsuneyasu Kaisho, Johanna Kaufmann, Kristen McEachern, Hatem Soliman, Vincent C Luca, Paulo C Rodriguez, Xiaoqing Yu, Brian Ruffell
• Journal: Immunity (Immunity) Vol. 54 Issue 6 Pg. 1154-1167.e7 (06 08 2021) ISSN: 1097-4180 [Electronic] United States
• PMID: 33979578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Chemokines
• Havcr2 protein, mouse
• Hepatitis A Virus Cellular Receptor 2
• Membrane Proteins
• Sting1 protein, mouse
• DNA
• Nucleotidyltransferases
• cGAS protein, mouse

Topics

• Animals
• Biological Transport (physiology)
• Cell Line
• Cell Line, Tumor
• Chemokines (metabolism)
• Cytoplasm (metabolism)
• DNA (metabolism)
• Dendritic Cells (metabolism)
• Endocytosis (physiology)
• Female
• HEK293 Cells
• Hepatitis A Virus Cellular Receptor 2 (metabolism)
• Humans
• Immunotherapy (methods)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Nucleotidyltransferases (metabolism)
• Signal Transduction (physiology)