title: CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer.
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.
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Biotherapy, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Ye
authors.affiliation: Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: M-X
authors.initials: MX
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Biotherapy, Guangzhou, China.
authors.forename: S-B
authors.initials: SB
authors.lastname: Ye
authors.affiliation: Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: W-R
authors.initials: WR
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Biotherapy, Guangzhou, China.
authors.forename: T-T
authors.initials: TT
authors.lastname: Cai
authors.affiliation: Department of Biotherapy, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Biotherapy, Guangzhou, China.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: T-H
authors.initials: TH
authors.lastname: Duan
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Biotherapy, Guangzhou, China.
authors.forename: X-S
authors.initials: XS
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: F-J
authors.initials: FJ
authors.lastname: Zhou
authors.affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA.|Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA.
authors.forename: R-F
authors.initials: RF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, China.|Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|Department of Biotherapy, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
mesh_terms: D016022:Case-Control Studies; D045744:Cell Line, Tumor; D054426:Chemokine CXCL2 / Q000378:metabolism*; D002633:Chemotaxis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D022423:Myeloid Cells / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; D008263:Macrophage Migration-Inhibitory Factors; D023063:Receptors, Interleukin-8B; D063268:Sialic Acid Binding Ig-like Lectin 3; D051996:Transcription Factor RelA; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human