Malignant ascite-derived extracellular vesicles inhibit T cell activity by upregulating Siglec-10 expression
Authors Li Y, Zhou J, Zhuo Q, Zhang J, Xie J, Han S, Zhao S
Received 30 March 2019
Accepted for publication 4 July 2019
Published 29 July 2019 Volume 2019:11 Pages 7123—7134
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Eileen O'Reilly
Yujuan Li,1,* Jing Zhou,1,* Qian Zhuo,2 Jingyun Zhang,1 Jingyan Xie,1 Suping Han,3 Shuli Zhao1,4
1Department of Obstetrics and Gynecology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Pathology, Xuzhou Medical College, Xuzhou, Jiangsu, People’s Republic of China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 4State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
*These authors contributed equally to this work
Background and purpose: To evade immune defense, cancer cells can employ extracellular vesicles (EVs) to inhibit the anti-tumor activity of lymphocytes in the tumor microenvironment. However, the mechanisms and key molecules that mediate the effects of EVs on lymphocytes are unclear.
Patients and methods: We used Quantibody® Human Cytokine Antibody Array 440 to determine the tumor immunity-related cytokine profile of peripheral blood lymphocytes (PBLs) stimulated with EVs derived from peritoneal washes or malignant ascites. We detected 21 upregulated and 27 downregulated proteins, including the immunosuppressive receptors Siglec-10, SLAM, PD-1, and TIM-3.
Results: Flow cytometry analysis of PBLs or ovarian cancer ascites suggested that Siglec-10 expression on CD3+ T cells was higher in ovarian cancer patients than in healthy controls and in the malignant ascites of ovarian cancer patients than in their blood. Moreover, the expression of CD24, the Siglec-10 ligand, was associated with tumor stage and cancer cell metastasis. Finally, compared to the benign peritoneal wash-derived EVs, the malignant EVs significantly upregulated Siglec-10 expression on Jurkat T cells, inhibited the protein kinase C activity induced by phorbol 12-myristate 13-acetate and ionomycin, and impaired the phosphorylation of the tyrosine kinase ZAP-70 activated by crosslinking with an anti-CD3 antibody.
Conclusion: The EVs secreted by malignant ovarian cells upregulated Siglec-10 expression on T cells and impaired T cell activation in the tumor microenvironment. We believe that a comprehensive understanding of the regulation of Siglec-10 and CD24 by malignant EVs has clinical importance, as it will aid in the development of better immunotherapeutic strategies for ovarian cancer.
Keywords: extracellular vesicles, Siglec-10, T cells, ovarian cancer, ascites
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