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; Jakub Golab

doi:10.1038/s41467-019-10979-3

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

Nat Commun. 2019 Jul 5;10(1):3000. doi: 10.1038/s41467-019-10979-3.

Authors

Malgorzata Czystowska-Kuzmicz¹, Anna Sosnowska^{1

2}, Dominika Nowis^{1

3

4}, Kavita Ramji¹, Marta Szajnik^{5

6}, Justyna Chlebowska-Tuz³, Ewa Wolinska⁷, Pawel Gaj⁸, Magdalena Grazul¹, Zofia Pilch¹, Abdessamad Zerrouqi¹, Agnieszka Graczyk-Jarzynka¹, Karolina Soroczynska¹, Szczepan Cierniak⁹, Robert Koktysz⁹, Esther Elishaev¹⁰, Slawomir Gruca¹, Artur Stefanowicz¹¹, Roman Blaszczyk¹², Bartlomiej Borek¹², Anna Gzik¹², Theresa Whiteside^{10

13}, Jakub Golab^{14

15}

Affiliations

¹ Department of Immunology, Medical University of Warsaw, Warsaw, 02-097, Poland.
² School of Molecular Medicine, Medical University of Warsaw, Warsaw, 02-091, Poland.
³ Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Warsaw, 02-097, Poland.
⁴ Genomic Medicine, Medical University of Warsaw, Warsaw, 02-097, Poland.
⁵ Holy Family Obstetrics and Gynecology Hospital, Warsaw, 02-544, Poland.
⁶ Institute of Mother and Child, Obstetrics and Gynaecology Clinic, Warsaw, 01-211, Poland.
⁷ Department of Pathology, Medical University of Warsaw, Warsaw, 02-142, Poland.
⁸ Laboratory of Human Cancer Genetics, Center of New Technologies, University of Warsaw, Warsaw, 02-097, Poland.
⁹ Department of Gynecology and Gynecologic Oncology, Military Institute of Medicine, Warsaw, 04-141, Poland.
¹⁰ Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, 15123, PA, USA.
¹¹ Department of Gynecology and Obstetrics, "Praski" Hospital, Warsaw, 03-401, Poland.
¹² OncoArendi Therapeutics, Warsaw, 02-089, Poland.
¹³ Department of Immunology and Otorhinolaryngology, UPMC Hillman Cancer Center, Pittsburgh, 15213, PA, USA.
¹⁴ Department of Immunology, Medical University of Warsaw, Warsaw, 02-097, Poland. [email protected].
¹⁵ Centre of Preclinical Research, Medical University of Warsaw, Warsaw, 02-091, Poland. [email protected].

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.

Publication types

Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arginase / antagonists & inhibitors
Arginase / immunology
Arginase / metabolism*
Ascites / immunology
Ascites / pathology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cell Communication / immunology
Cell Line, Tumor / transplantation
Cell Proliferation / drug effects
Cohort Studies
Datasets as Topic
Dendritic Cells / immunology
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Extracellular Vesicles / immunology*
Extracellular Vesicles / metabolism
Female
Humans
Kaplan-Meier Estimate
Lymphocyte Activation / drug effects
Lymphocyte Activation / immunology
Mice
Middle Aged
Ovarian Neoplasms / blood
Ovarian Neoplasms / immunology*
Ovarian Neoplasms / mortality
Ovarian Neoplasms / pathology
Tumor Escape / immunology*

Substances

Enzyme Inhibitors
ARG1 protein, human
Arg1 protein, mouse
Arginase

Abstract

Publication types

MeSH terms

Substances

Grants and funding