The role of regulatory B cells on hepatocellular carcinoma progression

Abstract

PURPOSE: Regulatory B cells (Bregs) play important roles in autoimmune diseases, but their function in hepatocellular carcinoma (HCC) progression remains unclear. This study attempted to unveil the role of Bregs on HCC progression. EXPERIMENTAL DESIGN: This study examined the distribution of intrahepatic B cells and circulating Bregs population at the level of phenotypes as well as functionality in HCC patients. The mechanisms of Bregs regulating liver tumor cells were further explored in a series of in vitro and in vivo functional studies. RESULTS: The percentage of B cells at tumor margin region was significantly higher than that in tumor or non-tumor region. Increased intrahepatic B cells at tumor margin were positively associated with tumor invasive features and more tumor recurrence. Besides, HCC patients had a significant higher percentage of circulating Bregs than healthy people. Increased circulating Bregs were positively correlated with advanced tumor staging, tumor multiplicity and venous infiltration. Next, our in vivo study firstly revealed that human Bregs promoted HCC tumor growth independent of Tregs in SCID mice. The migration of Bregs into tumor in mice was further confirmed by in vivo imaging and histology. Finally, the molecular mechanism of Bregs promoted proliferation and migration of HCC cells was proved by direct cell-cell interaction via CD40/CD154 signaling in vitro. Coculture of Bregs and HCC cells induced CD40/CD154-dependent cytokines secretion. CONCLUSION: Human Bregs promoted HCC growth and invasiveness by interacting with HCC tumor cells through CD40/CD154 signaling pathway. Bregs might be both a prognostic marker and a therapeutic target for HCC.