STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients

J Clin Invest. 2013 Apr;123(4):1580-9. doi: 10.1172/JCI60083.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginase / genetics*
  • Arginase / metabolism
  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme Repression
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • HLA-DR Antigens / metabolism
  • Head and Neck Neoplasms / enzymology*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Lipopolysaccharide Receptors / metabolism
  • Myeloid Cells / enzymology*
  • Myeloid Cells / pathology
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Processing, Post-Translational
  • RNA, Small Interfering / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • STAT3 Transcription Factor / physiology*
  • Superoxides / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology

Substances

  • HLA-DR Antigens
  • Lipopolysaccharide Receptors
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Superoxides
  • Arginase
  • arginase I, human