机构:[1]State Key Laboratory of Oncology in South China, Guangzhou, China其他部门华南肿瘤学国家重点实验室中山大学肿瘤防治中心[2]Collaborative Innovation Center of Cancer Medicine, Guangzhou, China[3]Department of Biotherapy, Guangzhou, China[4]Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China临床科室泌尿外科中山大学肿瘤防治中心[5]Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China[6]Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-sen University, Guangzhou, China[7]Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA[8]Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA.
The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33(+) MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P < 0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33(+) MDSCs (P < 0.01). Subsequently, we demonstrated that CD45(+) CD33(+) CD11b(+) HLA-DR-MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45(+) CD33+ CD11b(+) HLA-DR -MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P < 0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.
基金:
National Key Basic Research Program of China of the National Natural Science Foundation of China [2014CB745200]; Shenzheng City Science Foundation [81572982, 81372442, 81172164, 2014041470821172]
语种:
外文
被引次数:
WOS:
PubmedID:
中科院(CAS)分区:
出版当年[2017]版:
大类|1 区医学
小类|1 区遗传学2 区生化与分子生物学2 区细胞生物学2 区肿瘤学
最新[2023]版:
大类|1 区医学
小类|1 区生化与分子生物学1 区遗传学2 区细胞生物学2 区肿瘤学
第一作者:
第一作者机构:[1]State Key Laboratory of Oncology in South China, Guangzhou, China[2]Collaborative Innovation Center of Cancer Medicine, Guangzhou, China[3]Department of Biotherapy, Guangzhou, China
通讯作者:
通讯机构:[1]State Key Laboratory of Oncology in South China, Guangzhou, China[2]Collaborative Innovation Center of Cancer Medicine, Guangzhou, China[3]Department of Biotherapy, Guangzhou, China[7]Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA[8]Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA.[*1]Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, 1300 York Avenue, New York, NY 10065, USA[*2]Cancer Center, Sun Yatsen University, 651 Dongfeng East Road, Guangzhou 510060, China.
推荐引用方式(GB/T 7714):
Zhang H.,Ye Y-L,Li M-X,et al.CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer[J].ONCOGENE.2017,36(15):2095-2104.doi:10.1038/onc.2016.367.
APA:
Zhang, H.,Ye, Y-L,Li, M-X,Ye, S-B,Huang, W-R...&Li, J..(2017).CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer.ONCOGENE,36,(15)
MLA:
Zhang, H.,et al."CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer".ONCOGENE 36..15(2017):2095-2104