期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 97, 期 1, 页码 191-200出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.5A1113-626RR
关键词
iNOS; nitric oxide; MDSC; neurotransmitter; cancer; immune suppression
资金
- National Natural Science Foundation of China [81201602]
- Shanghai Pujiang Program [12PJ1407600]
- Scientific Foundation of Shanghai Health Bureau [20114138]
- Scientific Research Foundation for Returned Scholars (Ministry of Education of China)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition [11DZ2260500]
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-gamma production via D1-like DA receptors and retarded tumor growth. DA and other D1 receptor agonists inhibited IFN-gamma-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.
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