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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.

SUBMITTER: de Mingo Pulido A

PROVIDER: S-EPMC8192496 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

de Mingo Pulido Álvaro Á Hänggi Kay K Celias Daiana P DP Gardner Alycia A Li Jie J Batista-Bittencourt Bruna B Mohamed Eslam E Trillo-Tinoco Jimena J Osunmakinde Olabisi O Peña Reymi R Onimus Alexis A Kaisho Tsuneyasu T Kaufmann Johanna J McEachern Kristen K Soliman Hatem H Luca Vincent C VC Rodriguez Paulo C PC Yu Xiaoqing X Ruffell Brian B

Immunity 20210511 6

Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1<sup>+</sup> 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 impai ...[more]

PMID: 33979578

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Project description:BackgroundIntratumor-resident bacteria represent an integral component of the tumor microenvironment (TME). Microbial dysbiosis, which refers to an imbalance in the bacterial composition and bacterial metabolic activities, plays an important role in regulating breast cancer development and progression. However, the impact of specific intratumor-resident bacteria on tumor progression and their underlying mechanisms remain elusive.Methods16S rDNA gene sequencing was used to analyze the cancerous and paracancerous tissues from breast cancer patients. The mouse models of bearing 4T1 cell tumors were employed to assess the influence of bacterial colonization on tumor growth. Tissue infiltration of regulatory T (Treg) cells and CD8+ T cells was evaluated through immunohistochemistry and flow cytometric analysis. Comparative metabolite profiling in mice tumors was conducted using targeted metabolomics. Differential genes of tumor cells stimulated by bacteria were analyzed by transcriptomics and validated by qPCR assay.ResultsWe found that Sphingobacterium displayed high abundance in cancerous tissues. Intra-tumoral colonization of Sphingobacterium multivorum (S. multivorum) promoted tumor progression in 4T1 tumor-bearing mice. Moreover, S. multivorum diminished the therapeutic efficacy of αPD-1 mAb, which was associated with the increase of regulatory T cell (Treg) infiltration, and decrese of the CD8+ T cell infiltration. Targeted metabolomics revealed a conspicuous reduction of propionylcarnitine in tumors colonized by S. multivorum Furthermore, the combination of metabolite propionylcarnitine and S. multivorum shown to suppress tumor growth compared that in S. multivorum alone in vivo. Mechanistically, S. multivorum promoted the secretion of chemokines CCL20 and CXCL8 from tumor cells. CCL20 secreted into the TME facilitated the recruitment of Treg cells and reduced CD8+ T cell infiltration, thus promoting tumor immune escape.ConclusionsThis study reveals S. multivorum suppresses immune surveillance within the TME, thereby promoting breast cancer progression.

Dataset Information

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

Publications

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

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