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Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

ABSTRACT: Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4+ and CD8+ T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule - ARG1, mitigating anti-tumor immune responses.

SUBMITTER: Czystowska-Kuzmicz M

PROVIDER: S-EPMC6611910 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

Czystowska-Kuzmicz Malgorzata M Sosnowska Anna A Nowis Dominika D Ramji Kavita K Szajnik Marta M Chlebowska-Tuz Justyna J Wolinska Ewa E Gaj Pawel P Grazul Magdalena M Pilch Zofia Z Zerrouqi Abdessamad A Graczyk-Jarzynka Agnieszka A Soroczynska Karolina K Cierniak Szczepan S Koktysz Robert R Elishaev Esther E Gruca Slawomir S Stefanowicz Artur A Blaszczyk Roman R Borek Bartlomiej B Gzik Anna A Whiteside Theresa T Golab Jakub J

Nature communications 20190705 1

Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4<sup>+</sup> and CD8<sup>+</sup> T-cells in vi ...[more]

PMID: 31278254

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Project description:Paracrine signaling between tumor and surrounding stromal cells is critical for the maintenance of tumor microenvironment during ovarian cancer progression. Small extracellular vesicles (sEVs; exosomes in particular) are nano-sized vesicles secreted actively by many cells including tumor cells and are found to have fundamental roles in intercellular communication through shuttling functional RNAs. Although microRNAs (also called miRNAs or miRs), small non-coding RNAs regulating gene expression, are selectively accumulated in tumor sEVs and can mediate intercellular communication, the exact biological mechanisms underlying the functions of exosomal miRNAs in ovarian tumor angiogenesis remain unclear. In this study, sEVs were isolated from conditioned medium of the human ovarian carcinoma cell line SKOV-3 using ExoQuick Exosome Precipitation Solution, and characterized by scanning electron microscopy, dynamic light scattering, and immunoblotting. To elucidate the possible paracrine effects on ovarian tumor cell-derived sEVs (TD-sEVs), we investigated the angiogenesis-related signaling events triggered by TD-sEVs in endothelial cells. Due to the possible role in ovarian tumor pathogenesis, we focused on miR-141-3p which was detected to be enriched in TD-sEVs compared with their corresponding donor cells. We identified that sEV transfer of miR-141-3p considerably reduced the expression levels of cytokine-inducible suppressors of cytokine signaling (SOCS)-5 leading to up-regulated JAK-STAT3 pathway in endothelial cells. We also observed that sEV-shuttled miR-141-3p may up-regulate the expression of VEGFR-2 in endothelial cells which leads to promoting endothelial cell migration and angiogenesis. The putative role of miR-141-3p shuttled by TD-sEVs in regulating VEGFR-2 expression was demonstrated by the ability of anti-miR-141-3p to rescue the promoting effects of TD-sEVs on the expression of VEGFR-2 in endothelial cells. Our results also revealed that TD-sEVs trigger the intracellular reactive oxygen species (ROS)-dependent activation of NF-?B signaling in endothelial cells. Taken together, our findings propose a novel model in which sEV transfer of epithelial ovarian cancer-secreted miR-141-3p plays as a significant mediator of intercellular communication, promoting endothelial cell angiogenesis.

Dataset Information

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

Publications

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

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