title: Transmembrane tumor necrosis factor-α promotes the recruitment of MDSCs to tumor tissue by upregulating CXCR4 expression via TNFR2.
abstract: Myeloid-derived suppressor cells (MDSCs) accumulated in tumor sites promote immune evasion. We found that TNFR deficiency-induced rejection of transplanted tumor was accompanied with markedly decreased accumulation of MDSCs. However, the mechanism(s) behind this phenomenon is not completely understood. Here, we demonstrated that TNFR deficiency did not affect the amount of MDSCs in bone marrow (BM), but decreased accumulation of Gr-1+CD11b+MDSCs in the spleen and tumor tissues. The chemotaxis of Tnfr-/-MDSCs was prominently decreased in response to both tumor cell culture supernatants and tumor tissue homogenates from Tnfr-/-and wild-type mice, indicating an effect of TNFR signaling on chemokine receptor expression in MDSCs. We used real-time PCR to detect gene expression for several chemokine receptors in MDSCs from BM and found that CXCR4 was the most affected molecule at the transcriptional level in Tnfr-/-MDSCs. Neutralizing CXCR4 in wild-type MDSCs by a specific antibody blocked their chemotactic migration. Interestingly, it was tmTNF-α, but not sTNF-α, that induced CXCR4 expression in MDSCs. This effect of tmTNF-α was totally blocked in TNFR2-/-but not in TNFR1-/-MDSCs, and partially inhibited by PDTC or SB203580, an inhibitor of NF-κB or p38 MAPK pathway, respectively. Adoptive transfer of wild-type MDSCs restored MDSCs accumulation in tumors of Tnfr-/-mice, but this could be partially blocked by treatment with a CXCR4 inhibitor AMD3100. Our data suggest that tmTNF-α upregulates CXCR4 expression that promotes chemotaxis of MDSCs to tumor, and give a new insight into a novel mechanism by which tmTNF-α facilitates tumor immune evasion.
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: bhpsky@163.com.
authors.forename: Hongping
authors.initials: H
authors.lastname: Ba
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Hematology, Yichang Central People's Hospital, Yichang, Hubei 443003, China. Electronic address: libaihua1986@126.com.
authors.forename: Baihua
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: lxyfly2003@163.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: licheng.0419@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: 543683753@qq.com.
authors.forename: Anlin
authors.initials: A
authors.lastname: Feng
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: zhuyz0918@163.com.
authors.forename: Yazhen
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: wangjhxh@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: zhuoyali@mails.tjmu.edu.cn.
authors.forename: Zhuoya
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Immunology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: bingjiao.yin@hust.edu.cn.
authors.forename: Bingjiao
authors.initials: B
authors.lastname: Yin
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D000067996:RAW 264.7 Cells; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics; D019139:Tumor Escape; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; D016328:NF-kappa B; D019718:Receptors, CXCR4; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CXCR4; Chemotaxis; Myeloid-derived suppressor cells (MDSC); TNF receptor; Transmembrane tumor necrosis factor-α; Tumor