CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer

H. Zhang, Y. L. Ye, M. X. Li, S. B. Ye, W. R. Huang, T. T. Cai, J. He, J. Y. Peng, T. H. Duan, J. Cui, X. S. Zhang, F. J. Zhou, R. F. Wang, J. Li

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2095-2104
Number of pages10
JournalOncogene
Volume36
Issue number15
DOIs
StatePublished - Apr 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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