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

被引：249

作者：

Czystowska-Kuzmicz, Malgorzata ^{[1
]}

Sosnowska, Anna ^{[1
,2
]}

Nowis, Dominika ^{[1
,3
,4
]}

Ramji, Kavita ^{[1
]}

Szajnik, Marta ^{[5
,6
]}

Chlebowska-Tuz, Justyna ^{[3
]}

Wolinska, Ewa ^{[7
]}

Gaj, Pawel ^{[8
]}

Grazul, Magdalena ^{[1
]}

Pilch, Zofia ^{[1
]}

Zerrouqi, Abdessamad ^{[1
]}

Graczyk-Jarzynka, Agnieszka ^{[1
]}

Soroczynska, Karolina ^{[1
]}

Cierniak, Szczepan ^{[9
]}

Koktysz, Robert ^{[9
]}

Elishaev, Esther ^{[10
]}

Gruca, Slawomir ^{[1
]}

Stefanowicz, Artur ^{[11
]}

Blaszczyk, Roman ^{[12
]}

Borek, Bartlomiej ^{[12
]}

Gzik, Anna ^{[12
]}

Whiteside, Theresa ^{[10
,13
]}

Golab, Jakub ^{[1
,14
]}

机构：

[1] Med Univ Warsaw, Dept Immunol, PL-02097 Warsaw, Poland

[2] Med Univ Warsaw, Sch Mol Med, PL-02091 Warsaw, Poland

[3] Univ Warsaw, Ctr New Technol, Lab Expt Med, PL-02097 Warsaw, Poland

[4] Med Univ Warsaw, Genom Med, PL-02097 Warsaw, Poland

[5] Holy Family Obstet & Gynecol Hosp, PL-02544 Warsaw, Poland

[6] Inst Mother & Child Hlth, Obstet & Gynaecol Clin, PL-01211 Warsaw, Poland

[7] Med Univ Warsaw, Dept Pathol, PL-02142 Warsaw, Poland

[8] Univ Warsaw, Ctr New Technol, Lab Human Canc Genet, PL-02097 Warsaw, Poland

[9] Mil Inst Med, Dept Gynecol & Gynecol Oncol, PL-04141 Warsaw, Poland

[10] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15123 USA

[11] Praski Hosp, Dept Gynecol & Obstet, PL-03401 Warsaw, Poland

[12] OncoArendi Therapeut, PL-02089 Warsaw, Poland

[13] UPMC Hillman Canc Ctr, Dept Immunol & Otorhinolaryngol, Pittsburgh, PA 15213 USA

[14] Med Univ Warsaw, Ctr Preclin Res, PL-02091 Warsaw, Poland

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

欧盟地平线“2020”;

关键词：

L-ARGININE; CANCER; EXPRESSION; EXOSOMES; MICROENVIRONMENT; APOPTOSIS; IMMUNOSUPPRESSION; IMMUNOTHERAPY; CHEMOTHERAPY; LYMPHOCYTES;

D O I：

10.1038/s41467-019-10979-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

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