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

作者：Wu, Liangliang; Deng, Zhaoyang; Peng, Yaojun; Han, Lu; Liu, Jing; Wang, Linxiong; Li, Bohua; Zhao, Jian; Jiao, Shunchang^*; Wei, Huafeng^*

来源：Oncotarget, 2017, 8(44): 76843-76856.

DOI：10.18632/oncotarget.20164

• MDSC
• ovarian cancer
• IL-6
• IL-10
• STAT3

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.

• 出版日期2017-9-29
• 单位上海大学; 中国人民解放军总医院