CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer
CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer
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CXCL2/MIF-CXCR2 信号传导促进骨髓源性抑制细胞的募集并与膀胱癌的预后相关
DOI：
10.1038/onc.2016.367
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发表时间：
2017-04-13
期刊：
影响因子：
8
通讯作者：
Li, J.
中科院分区：
文献类型：
--
作者：
Zhang, H.;Ye, Y-L;Li, J.
骨髓源性抑制细胞（MDSC）的积累已在实体瘤中观察到，并与肿瘤进展相关;然而，其潜在机制仍知之甚少。在这项研究中，我们确定了肿瘤细胞通过CXCL 2/MIF-CXCR 2信号传导诱导膀胱癌（BC）微环境中MDSC积聚和扩增的机制。BC组织中CXCL 2和MIF表达增高，CD 33（+）MDSCs数量增多，且与疾病分期及预后不良相关（P < 0.01）。CXCL 2和MIF的表达与肿瘤浸润的CD 33（+）MDSC数量呈正相关（P < 0.01）。随后，我们证明了来自新鲜BC组织的CD 45（+）CD 33（+）CD 11b（+）HLA-DR-MDSCs显示出高水平的抑制分子，包括Arg 1，iNOS，ROS，PDL-1和P-STAT 3，以及更强的T细胞增殖抑制。CD 45（+）CD 33 + CD 11b（+）HLA-DR -MDSCs中CXCR 2的表达明显高于BC患者和健康对照组（P < 0.05）。体外趋化实验表明，膀胱癌细胞系J82通过CXCL 2/MIF-CXCR 2信号通路诱导MDSC迁移。机制研究表明，J82诱导的MDSC运输和CXCR 2表达与p38，ERK和p65磷酸化增加有关。相反，抑制p38、ERK或p65的磷酸化降低了J82诱导的MDSC运输和CXCR 2表达。在MDSC中，CXCL 2/MIF刺激的丝裂原活化蛋白激酶和核因子κ B途径的活化是MyD 88依赖性的。总体而言，我们的研究结果确定CXCL 2/MIF-CXCR 2轴作为MDSC募集的重要介质，并作为BC患者的预测因子和潜在治疗靶点。
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.