Activated hepatic stellate cells (HSCs) play a central role in the hepatic fibrosis and cirrhosis. Recently, HSCs were reported to have strong immune modulatory activities. However, the role of HSCs in hepatocellular carcinoma (HCC) remains unclear. In this study, we showed that HSCs could promote HCC growth both in vitro and in vivo. We examined the HSC-mediated inhibition of T-cell proliferation and the ability of conditioned medium from activated HSCs to promote the growth of murine HCC cell lines in vitro. We also assessed the immune suppression by HSCs during the development of HCC in immunocompetent mice. Cotransplantation of HSCs promoted HCC growth and progression by enhancing tumor angiogenesis and tumor cell proliferation and by creating an immunosuppressed microenvironment. Cotransplanted HSCs inhibited the lymphocyte infiltration in tumors and the spleens of mice bearing tumors, induced apoptosis of infiltrating mononuclear cells, and enhanced the expression of B7H1 and CD4 1 CD25 1 Treg cells. The immune modulation by HSCs seemed to be systemic. In conclusion, our data provide new information to support an integral role for HSCs in promoting HCC progression in part via their immune regulatory activities, and suggest that HSCs may serve as a therapeutic target in HCC.Hepatocellular carcinoma (HCC), a common malignant tumor worldwide, is a severe public health concern. 1 Carcinogenesis of HCC is a multifactor, multistep and complex process. Recently, many studies have demonstrated that hepatic fibrosis and liver cirrhosis, which are the ultimate results of chronic liver disease, are closely associated with HCC. 2 Liver fibrosis, cirrhosis and HCC all arise from liver parenchymal cells and mesenchymal cells. 3 Genetic and cellular biological studies on malignant tumors have shown that the interaction between parenchymal and stromal cells are important for tumor formation and development. 4 Stromal cells include myofibroblasts and endothelial cells, both of which interact with parenchymal cells via (1) the secretion of cytokines and other chemical factors, (2) extra cellular matrix (ECM)-mediated interaction and (3) direct cell-to-cell contiguity. 5 Stromal cells are closely related to angiogenesis, cancer desmoplasia and tumor immunity and are therefore important players in the progression, growth and spread of tumors. 6 Furthermore, several studies have shown that tumor cells can further induce the expression of tumorigenic factors in tumor-associated stromal cells, 7,8 indicating a mutual interaction between cancer cells and stromal cells. Thus, studies on the role of tumor stroma in the development and progression of cancer will help to clarify the mechanisms of carcinogenic lesions and lead to more effective therapeutic approaches.Hepatic stellate cells (HSCs) are the main collagen-producing cells in the injured liver. 9 Following a chronic liver injury, HSCs play important roles during the development of

Hepatic stellate cells (HSCs) have immunosuppressive abilities and may be responsible for the occurrence and development of hepatocellular carcinoma (HCC). However, the mechanisms through which HSCs affect T-cell-mediated immune responses remain unclear. The aim of this study was to elucidate these mechanisms. We examined the effect of HSCs on T-cell proliferation and apoptosis, regulatory T cells (Treg cells) and T-cell-mediated cytotoxicity using mixed leukocyte reactions (MLRs). Furthermore, we examined the cytokines present in the supernatant and the effect of this supernatant on the proliferation and migration of cancer cells. Finally, we examined the effect of HSCs on HCC cells in vivo. We found that activated HSCs induced T-cell hyporesponsiveness, accelerated activated T-cell apoptosis, increased the number of Treg cells and inhibited T-cell-mediated cytotoxicity. HSCs also enhanced the expression of some cytokines and promoted the proliferation and migration of cancer cells. Furthermore, activated HSCs were able to induce HCC proliferation and Treg cells expansion in vivo. Activated HSCs may induce T cell anergy, thereby facilitating the immunologic escape of HCC cells.

Hepatic stellate cells (HSCs) have immunosuppressive capabilities and contribute to the occurrence and development of hepatocellular carcinoma (HCC). Thus, activated HSCs may be a suitable target for HCC therapy. Our study used mixed leukocyte reactions (MLR) in vitro to demonstrate that 18β‐glycyrrhetinic acid (GA) could reverse HSC‐mediated immunosuppression by reducing T‐cell apoptosis and regulatory T (Treg) cells expression, thereby enhancing the ability of T cells to attack tumor cells and attenuating HCC cell invasiveness. Moreover, we established a HCC orthotopic implantation model in immunocompetent C57BL/6 mice, which suggested that GA played a protective role in HCC development by reducing immunosuppression mediated by HSCs in the tumor microenvironment.