title: Dopamine inhibits the function of Gr-1+CD115+ myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity.
abstract: MDSCs accumulate in tumor-bearing animals and cancer patients and are a major factor responsible for cancer-induced immunosuppression that limits effective cancer immunotherapy. Strategies aimed at effectively inhibiting the function of MDSCs are expected to enhance host anti-tumor immunity and improve cancer immunotherapy significantly. The neurotransmitter DA has been found to have anti-cancer activity, but the underlying mechanism is poorly understood. In this study, we sought to investigate the therapeutic mechanism and efficacy of DA on the inhibition of cancer development via the regulation of MDSC functions. The regulation of the suppressive function of Gr-1(+)CD115(+) MDSCs by DA was determined by use of murine syngeneic LLC and B16 graft models treated with DA in vivo, as well as Gr-1(+)CD115(+) MDSCs isolated from these model treated with DA ex vivo. Here, we show that Gr-1(+)CD115(+) monocytic MDSCs express D1-like DA receptors. DA dramatically attenuated the inhibitory function of tumor-induced monocytic MDSCs on T cell proliferation and IFN-γ production via D1-like DA receptors and retarded tumor growth. DA and other D1 receptor agonists inhibited IFN-γ-induced NO production by MDSCs from tumor-bearing mice and cancer patients. Decreased NO production was, in part, mediated via the suppression of p-ERK and p-JNK. In conclusion, the neurotransmitter DA potently inhibits the suppressive function of MDSC and enhances anti-tumor immunity. Our finding provides a mechanistic basis for the use of DA or D1-like receptor agonists to overcome tumor-induced immunosuppression in cancer immunotherapy.
authors.affiliation: Shanghai Institute for Pediatric Research and wujin51@yahoo.com caiw1978@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Shanghai Institute for Pediatric Research and.
authors.forename: Ning
authors.initials: N
authors.lastname: Tang
authors.affiliation: Shanghai Institute for Pediatric Research and.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Shanghai Institute for Pediatric Research and.
authors.forename: Jiefei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Shanghai Institute for Pediatric Research and Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Obstetrics and Gynecology, Immunology and Microbiology, Oncology, Wayne State University, Detroit, Michigan, USA; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, U.S. National Institutes of Health, Detroit, Michigan, USA; Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; and Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Shanghai Institute for Pediatric Research and wujin51@yahoo.com caiw1978@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D004298:Dopamine / Q000276:immunology* / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D017447:Receptors, Dopamine D1 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017447:Receptors, Dopamine D1; D004298:Dopamine
keywords: MDSC; cancer; iNOS; immune suppression; neurotransmitter; nitric oxide