IL-6 promotes MDSCs infiltration and immunosuppression in breast cancer by inducing SOCS3 deficiency
10.3872/j.issn.1007-385x.2018.09.004
- VernacularTitle:IL-6通过诱导SOCS3表达缺失促进乳腺癌MDSCs浸润和免疫抑制活性
- Author:
CHENG Yanan
1
;
JIANG Mengmeng
2
;
ZHANG Wenwen
2
;
LIU Pengpeng
1
;
ZHANG Rui
1
;
YU Jinpu
2
Author Information
1. Cancer Molecular Diagnostics Center
2. Cancer Molecular Diagnostics Center; b. Department of Immunology, Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Clinical Research Center for Malignant Cancer of Tianjin City
- Publication Type:Journal Article
- Keywords:
breast cancer;
myeloid-derived suppressor cells (MDSCs);
IL-6;
JAK/STATsignaling pathway;
suppressors of cytokine signalling(SOCS)
- From:
Chinese Journal of Cancer Biotherapy
2018;25(9):865-871
- CountryChina
- Language:Chinese
-
Abstract:
Objective: To investigate the immunosuppressive effect and underlying molecular mechanisms of Myeloid-derived suppressor cells (MDSCs) on T cells activity through IL-6activatingSTAT3/IDO signaling pathway. Methods: Twenty pairs of cancer tissues and the corresponding adjacent normal tissues from breast cancer patients treated at Tianjin Medical University Cancer Institute and Hospital from November 2015 to February 2016 were collected for this study; in the meanwhile, peripheral blood samples from 40 healthy donorswere also collected. CD33+ cells in tumor tissues and CD33+ CD14 + cells in peripheral blood of helthy donors were sorted out with MicroBeads technology. CD33+ cells were in vitro co-cultured with breast cancer cell line MDA-MB-231 to induce MDSCs. Flow cytometry was used to detect the proportion of CD45+ CD13+CD33+CD14-CD15- MDSCs.Western Blotting was used to detect the expression ofSOCS1，SOCS3, JAK1, JAK2, TYK2, STAT1, STAT3 and their phosphorylation levels. qRT-PCR was used to detect the expression of IL-6 and SOCS1-3. CCK8 was used to detect the T cell proliferation. Annexin V staining was used to detect T cell apoptosis. ELISA was used to detect IL-10 and IFN-γ secreted by T cells. Results: There were MDSCs infiltration in all 20 cases of breast cancer tissues for different levels (15.3%~58.1%), with a mean level of (29.82± 11.46%); the infiltration of IL-6high group was significantly higher than that of the IL-6low group [（13.75±3.44） % vs（4.31±1.50） %， P< 0.05], indicating that IL-6 expression was positively correlated with MDSCs infiltration (R2=0.4399, P<0.01). In vitro experiments showed that tumor-derived IL-6 significantly promoted the generation and immunosuppressive activity of MDSCs (P<0.05), which could be reversed by the blocking of IL-6. In the meanwhile, the expression of SOCS3 in MDSCs that induced in vitro was absent, which can be inhibited by blocking IL-6 (P<0.05). Conclusion: The study has demonstrated that tumor-derived IL-6 stimulates the continuous activation of the JAK/STAT signaling pathway and the absence of SOCS3 expression in MDSCs, thereby promoting the infiltration, generation and immunological activity of MDSCs. Therefore, IL-6 signaling pathway can be used as therapeutic target to weaken MDSCs generation and reverse MDSCs activity.
- Full text:20180904.pdf
