title: CCR5 Blockade Suppresses Melanoma Development Through Inhibition of IL-6-Stat3 Pathway via Upregulation of SOCS3.
abstract: In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, we found that chemokine receptor 5 (CCR5) neutralization resulted in reduced melanoma tumor size, decreased percentage of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs), and increased proportion of cluster of differentiation (CD)3+ T cells in tumor tissues. Suppressive activity of MDSCs on CD4+ T cells and CD8+ T cell proliferation is significantly inhibited by anti-CCR5 antibody. CCR5 blockade also suppresses interleukin (IL)-6 induction, which in turn deactivates signal transducer and activator of transcription 3 (Stat3) in tumors. Furthermore, the suppressed B16 tumor growth induced by CCR5 blockade is abolished with additional administration of recombinant IL-6. CCR5 blockade also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and anti-CCR5 antibody fails to suppress expression of phospho-Stat3 (p-Stat3), matrix metallopeptidase 9 (MMP9), and IL-6 in cells transfected with SOCS3 short-interfering RNA (SiRNA). All these data suggest that CCR5 blockade suppresses melanoma development through inhibition of IL-6-Stat3 pathway via upregulation of SOCS3.
authors.affiliation: Department of Oncology, Central Hospital of Wuhan, Wuhan Shengli Road 26#, Wuhan, Hubei, China. qiutangwhzxyy@163.com.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Oncology, Central Hospital of Wuhan, Wuhan Shengli Road 26#, Wuhan, Hubei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Oncology, People's Liberation Army, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D015850:Interleukin-6 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D034622:RNA Interference; D019713:Receptors, CCR5 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C000592874:CCR5 protein, mouse; D039481:CD11b Antigen; D017252:CD3 Complex; C503133:Gr-1 protein, mouse; D015850:Interleukin-6; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C577686:interleukin-6, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: CCR5; IL-6; SOCS3; Stat3; melanoma