Interaction of peripheral CD4+CD25+CD127− Tregs with prolactin in HCV hepatocellular carcinoma: oncogenic or immunogenic mechanisms

Abstract

Background and objective There is little and conflicting data about the peripheral CD4+CD25+CD127− Tregs in patients with hepatocellular carcinoma (HCC) of various etiologies. The expressed membrane-bound transforming growth factor (mTGF-β1) on these Tregs is a marker of their suppressive function. Prolactin suppresses Tregs function in healthy subjects but enhances local Tregs in breast cancer. Our study is the first to assess the frequency and function of CD4+CD25+CD127−Tregs and their association with clinicopathological features and staging in HCV-related HCC and to determine whether prolactin acts as an oncogenic growth factor or participates in the regulation of the immune response mediated by peripheral Tregs. In patients with HCV- elated HCC, HCV-cirrhotic patients, and healthy subjects, we measured the frequency of peripheral traditional CD4+ CD25+ Tregs and well-characterized CD4+CD25+CD127−Tregs and their mTGF-β1 using flow cytometric analysis and measured serum prolactin level. Results The frequency of CD4+ CD25+ and CD4+CD25+CD127− Tregs was comparable between HCC and cirrhotic patients and healthy subjects. Serum prolactin and mTGF-β1 on traditional and CD4+CD25+CD127− Tregs were significantly higher in HCC and cirrhotic patients than healthy subjects with an insignificant difference between HCC and cirrhotic patients. Roc curve analysis revealed that cutoff value for mTGF-β1 on Tregs ≥ 13.5% is a good specific (87%) but low sensitive (54%) test in discriminating HCC patients from healthy subjects. The frequency of Tregs and mTGF-β1 were not correlated to clinicopathological characteristics or staging of HCC. Prolactin was higher in the multifocal lesions and negatively correlated to expressed mTGFβ1. The expressed mTGF-β1 was positively correlated with hemoglobin and alanine transaminase. The traditional Tregs was positively correlated with hemoglobin and albumin. Conclusion mTGFβ1, as a marker for suppressive function of peripheral CD4 + CD25 + CD127-Tregs, has a diagnostic role in discriminating HCV-related HCC patient from healthy subjects, unfortunately not from HCV-related cirrhotic patients. Serum prolactin has an oncogenic role as it is correlated to multiple focal lesions. It also impedes the suppressive function of peripheral Tregs as an immunogenic role. mTGF-β1 is related to hemoglobin and hepatic inflammation.