STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients
David Vasquez-Dunddel, Fan Pan, Qi Zeng, Mikhail Gorbounov, Emilia Albesiano, Juan Fu, Richard L. Blosser, Ada J. Tam, Tullia Bruno, Hao Zhang, Drew Pardoll, Young Kim
David Vasquez-Dunddel, Fan Pan, Qi Zeng, Mikhail Gorbounov, Emilia Albesiano, Juan Fu, Richard L. Blosser, Ada J. Tam, Tullia Bruno, Hao Zhang, Drew Pardoll, Young Kim
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Research Article Oncology

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

David Vasquez-Dunddel, Fan Pan, Qi Zeng, Mikhail Gorbounov, Emilia Albesiano, Juan Fu, Richard L. Blosser, Ada J. Tam, Tullia Bruno, Hao Zhang, Drew Pardoll, Young Kim

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Figure 1

CD14+HLA-DR–/lo distribution and phenotypes in the blood, LNs, and tumors from HNSCC patients.

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CD14+HLA-DR–/lo distribution and phenotypes in the blood, LNs, and tumor...
(A) Relative abundance of circulating CD14+HLA-DR–/lo MDSC (with respect to CD11b+ cells prior to sorting in a given compartment) on HNSCC patients (SCCHN) (n = 20) versus patients with chronic tonsillitis (n = 9; **P < 0.01). The mean CD11b+ cells from these 2 patient populations were not statistically different. (B) Relative abundance of CD14+HLA-DR–/lo MDSC from PB (n = 37), DLNs (n = 10), and the primary tumor from HNSCC patients (n = 27; *P < 0.05, **P < 0.01). (C) Representative histograms of MDSC markers on CD14+HLA-DR–/lo cells from PB and tumor with isotype controls as shaded areas. The expression of CD33, CD34, CD14, and CD11b was similar between blood and tumor-infiltrating MDSC. There was a differential expression of CD15 in this population between PB and the primary tumor. (D) Circulating CD14+HLA-DR–/lo cells demonstrated skewing toward higher percentage of the HLA-DRint population, while the tumor and LNs had a greater percentage of the HLA-DR– phenotype (central and right panels, respectively). Numbers represent the percentages of cells in the indicated boxes.