title: STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients.
abstract: 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.
authors: Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21231, USA.
authors: David
authors: D
authors: Vasquez-Dunddel
authors: Fan
authors: F
authors: Pan
authors: Qi
authors: Q
authors: Zeng
authors: Mikhail
authors: M
authors: Gorbounov
authors: Emilia
authors: E
authors: Albesiano
authors: Juan
authors: J
authors: Fu
authors: Richard L
authors: RL
authors: Blosser
authors: Ada J
authors: AJ
authors: Tam
authors: Tullia
authors: T
authors: Bruno
authors: Hao
authors: H
authors: Zhang
authors: Drew
authors: D
authors: Pardoll
authors: Young
authors: Y
authors: Kim
mesh_terms: D001119:Arginase / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004794:Enzyme Repression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006684:HLA-DR Antigens / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D022423:Myeloid Cells / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
chemical_list: D006684:HLA-DR Antigens; D018950:Lipopolysaccharide Receptors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013481:Superoxides; C574619:ARG1 protein, human; D001119:Arginase