Reference - Detail
| RRC ID | 81803 |
|---|---|
| Author | de Mingo Pulido Á, Hänggi K, Celias DP, Gardner A, Li J, Batista-Bittencourt B, Mohamed E, Trillo-Tinoco J, Osunmakinde O, Peña R, Onimus A, Kaisho T, Kaufmann J, McEachern K, Soliman H, Luca VC, Rodriguez PC, Yu X, Ruffell B. |
| Title | The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake. |
| Journal | Immunity |
| 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. |
| Volume | 54(6) |
| Pages | 1154-1167.e7 |
| Published | 2021-6-8 |
| DOI | 10.1016/j.immuni.2021.04.019 |
| PII | S1074-7613(21)00181-3 |
| PMID | 33979578 |
| PMC | PMC8192496 |
| MeSH | 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* |
| Resource | |
| Mice | RBRC09485 |