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

Autor:	de Mingo Pulido Á; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Hänggi K; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Celias DP; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Gardner A; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA., Li J; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA., Batista-Bittencourt B; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA., Mohamed E; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Trillo-Tinoco J; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Osunmakinde O; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA; Department of Health Science and Technology, Aalborg University, Aalborg 29220, Denmark., Peña R; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Onimus A; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Molecular Medicine PhD Program, University of South Florida, Tampa, FL 33620, USA., Kaisho T; Institute for Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan., Kaufmann J; Immuno-Oncology & Combinations Research Unit, GSK, Waltham, MA 02451, USA., McEachern K; TESARO, Waltham, MA 02451, USA., Soliman H; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Luca VC; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Rodriguez PC; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Yu X; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Ruffell B; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: brian.ruffell@moffitt.org.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2021 Jun 08; Vol. 54 (6), pp. 1154-1167.e7. Date of Electronic Publication: 2021 May 11.
DOI:	10.1016/j.immuni.2021.04.019
Abstrakt:	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. Competing Interests: Declaration of interests This work was supported in part by a sponsored research agreement with TESARO. J.K. is an employee of GSK and K.M. was an employee of TESARO. H.S. has received payments from Novartis International AG for consulting and advisory boards. B.R. has received payments from Merck & Co. and Roche Farma S.A. for consulting. H.S., V.C.L., P.C.R., and B.R. have courtesy faculty appointments at the University of South Florida, Tampa. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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