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ARG1

-;arginase 1;ARG1;arginase 1

arginase, liver|arginase-1|liver-type arginase|type I arginase

6q23

protein-coding

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 MDSCs 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 MDSCs 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.

BACKGROUND: To investigate the correlation of Arg-1 expression with clinicopathologic factors and prognosis of HCC patients, including recurrence and survival rate. METHODS: We examined the expression of Arg-1 in HCC by immunohistochemistry and studied its correlation with a series of clinicopathologic features and prognositic parameters of patients with HCC. RESULTS: We found patients with higher Arg-1 expression showed less aggressive features based on less portal vein invasion (chi2 = 10.794, df = 1, p = 0.001), less microvessel invasion (chi2 = 4.247, df = 1, p = 0.039), lower TNM stage (chi2 = 4.992, df = 1, p = 0.025), and better differentiated histology (chi2 = 24.155, df= 1, p < 0.001). Among them, portal vein invasion (p = 0.024, 95% CI 1.010 - 2.321), microvessel invasion (p = 0.043, 95% CI 1.014 - 3.225), histology (p = 0.001, 95% CI 2.230 - 5.934), and TNM stage (p = 0.001, 95% CI 1.364 - 3.401) have been suggested as prognostic factors in HCC patients. Furthermore, the enhanced expression of Arg-1 in HCC appears to be associated with a lower recurrence rate and prolonged overall survival. CONCLUSIONS: These results suggest that Arg-1 may play a tumor suppressive role in HCC and could be a new, promising prognostic biomarker for HCC patients.