Oncotarget

Research Papers:

Ascites-derived IL-6 and IL-10 synergistically expand CD14+HLA-DR-/low myeloid-derived suppressor cells in ovarian cancer patients

Liangliang Wu, Zhaoyang Deng, Yaojun Peng, Lu Han, Jing Liu, Linxiong Wang, Bohua Li, Jian Zhao, Shunchang Jiao and Huafeng Wei _

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Oncotarget. 2017; 8:76843-76856. https://doi.org/10.18632/oncotarget.20164

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Abstract

Liangliang Wu1,*, Zhaoyang Deng2,*, Yaojun Peng1, Lu Han3, Jing Liu1, Linxiong Wang1, Bohua Li4, Jian Zhao4, Shunchang Jiao1,3 and Huafeng Wei1

1Key Lab of Cancer Center, General Hospital of Chinese PLA & Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, China

2Surgical Division, General Hospital of Chinese PLA, Beijing, China

3Department of Internal Oncology, General Hospital of Chinese PLA, Beijing, China

4Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China

*These authors have contributed equally to the work

Correspondence to:

Huafeng Wei, email: [email protected]

Shunchang Jiao, email: [email protected]

Keywords: MDSC, ovarian cancer, IL-6, IL-10, STAT3

Received: March 13, 2017   Accepted: June 27, 2017   Published: August 10, 2017

ABSTRACT

Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types of cancer, including ovarian cancer (OC). In this study, we characterized CD14+HLA-DR−/lo MDSC with a typical monocytic phenotype (M-MDSC) in the peripheral blood (PB) and ascites from OC patients. Compared to healthy donors, OC patients had a significantly increased abundance of M-MDSC in both PB and ascites; importantly, their abundance in both compartments was inversely associated with the prognosis where OC patients with higher level of M-MDSC having a shorter relapse-free survival. Intriguingly, we demonstrated that M-MDSC could be readily induced by ascitic fluids (AF) from OC patients, which was predominantly dependent on IL-6, IL-10 and STAT3 activation as neutralization of IL-6 and/or IL-10 or inhibition of STAT3 abrogated MDSC’s expansion while recombinant IL-6 and IL-10 recapitulated the expansive effect of AF; furthermore, predominantly elevated levels of IL-6 and IL-10 has been noted in the AF which was positively correlated with the abundance of M-MDSC as well as poor prognosis of OC patients. As expected, we observed that AF-driven STAT3 activation upregulated the expression of arginase (ARG1) and inducible nitric oxide synthase (iNOS) in induced M-MDSC through which these MDSC executed the immunosuppressive activity. Taken together, these results demonstrate that abundant M-MDSC are present in both periphery and ascites of OC patients whose accumulation and suppressive activity is critically attributable to ascites-derived IL-6 and IL-10 and their downstream STAT3 signal, thus providing a potentially novel therapeutic option by locally targeting MDSC to improve antitumor efficacy.


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