期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 4, 页码 1580-1589出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI60083
关键词
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资金
- NIH [K23-DE018464]
- Flight Attendant Medical Research Institute
- American College of Surgeons/Triological Career Developmental Grant
Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types of cancer, including head and neck squamous cell carcinoma (HNSCC). In this study, we characterized CD14(+)HLA-DR-/(lo) cells sorted from the tumors, draining lymph nodes, and peripheral blood of HNSCC patients. CD14(+)HLA-DR-/(lo) cells were phenotyped as CD11b(+), CD33(+), CD34(+), arginase-I+, and ROS+. In all 3 compartments, they suppressed autologous, antigen-independent T cell proliferation in a differential manner. The abundance of MDSC correlated with stage, but did not correlate with previous treatment with radiation or subsites of HNSCC. Interestingly, MDSC from all 3 compartments showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. Stattic, a STAT3-specific inhibitor, and STAT3-targeted siRNA abrogated MDSC's suppressive function. Inhibition of STAT3 signaling also resulted in decreased arginase-I activity. Analysis of the human arginase-I promoter region showed multiple STAT3-binding elements, and ChIP demonstrated that phosphorylated. STAT3 binds to multiple sites in the arginase-I promoter. Finally, rescue of arginase-I activity after STAT3 blockade restored MDSC's suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3.
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