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

  • Oncogene. 2017 Apr;36(15):2095-2104. doi: 10.1038/onc.2016.367.
H Zhang  1  2  3 ,  Y-L Ye  1  2  4 ,  M-X Li  5 ,  S-B Ye  1  2  3 ,  W-R Huang  5 ,  T-T Cai  1  2  3 ,  J He  3 ,  J-Y Peng  3 ,  T-H Duan  6 ,  J Cui  6 ,  X-S Zhang  1  2  3 ,  F-J Zhou  1  2  4 ,  R-F Wang  7  8 ,  J Li  1  2  3
Affiliations
  • 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.
  • 4. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 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.
PMID: 27721403 DOI: 10.1038/onc.2016.367
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.

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