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

Malgorzata Czystowska-Kuzmicz, Anna Sosnowska, Dominika Nowis, Kavita Ramji, Marta Szajnik, Justyna Chlebowska-Tuz, Ewa Wolinska, Pawel Gaj, Magdalena Grazul, Zofia Pilch, Abdessamad Zerrouqi, Agnieszka Graczyk-Jarzynka, Karolina Soroczynska, Szczepan Cierniak, Robert Koktysz, Esther Elishaev, Slawomir Gruca, Artur Stefanowicz, Roman Blaszczyk, Bartlomiej Borek, Anna Gzik, Theresa Whiteside and Jakub Golab ()
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Malgorzata Czystowska-Kuzmicz: Medical University of Warsaw
Anna Sosnowska: Medical University of Warsaw
Dominika Nowis: Medical University of Warsaw
Kavita Ramji: Medical University of Warsaw
Marta Szajnik: Holy Family Obstetrics and Gynecology Hospital
Justyna Chlebowska-Tuz: University of Warsaw
Ewa Wolinska: Medical University of Warsaw
Pawel Gaj: University of Warsaw
Magdalena Grazul: Medical University of Warsaw
Zofia Pilch: Medical University of Warsaw
Abdessamad Zerrouqi: Medical University of Warsaw
Agnieszka Graczyk-Jarzynka: Medical University of Warsaw
Karolina Soroczynska: Medical University of Warsaw
Szczepan Cierniak: Military Institute of Medicine
Robert Koktysz: Military Institute of Medicine
Esther Elishaev: University of Pittsburgh, School of Medicine
Slawomir Gruca: Medical University of Warsaw
Artur Stefanowicz: “Praski” Hospital
Roman Blaszczyk: OncoArendi Therapeutics
Bartlomiej Borek: OncoArendi Therapeutics
Anna Gzik: OncoArendi Therapeutics
Theresa Whiteside: University of Pittsburgh, School of Medicine
Jakub Golab: Medical University of Warsaw

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10979-3

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