Abstract
Hepatocellular carcinoma (HCC) is a leading cause of tumour-associated mortality worldwide, but no significant improvement in treating HCC has been reported with currently available systemic therapies. Immunotherapy represents a new frontier in tumour therapy. Therefore, the immunobiology of hepatocarcinoma has been under intensive investigation. Decoy receptor 3 (DcR3), a member of the tumour necrosis factor receptor (TNFR) superfamily, is an immune suppressor associated with tumourigenesis and cancer metastasis. However, little is known about the role of DcR3 in the immunobiology of hepatocarcinoma. In this study, we found that overexpression of DcR3 in HCC is mediated by the TGFβ3-Smad-Sp1 signalling pathway, which directly targets DcR3 promoter regions. Moreover, overexpression of DcR3 in HCC tissues is associated with tumour invasion and metastasis and significantly promotes the differentiation and secretion of Th2 and Treg cells while inhibiting the differentiation and secretion of Th1 cells. Conversely, knockdown of DcR3 expression in HCC significantly restored the immunity of CD4+ T cells. Inhibition of DcR3 expression may provide a novel immunotherapeutic approach to restoring immunity in HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a notably poor prognosis[1]
Expression of TGFβ3 and Decoy receptor 3 (DcR3) is upregulated in HCC The cytokine expression profile analysis between the samples from four patients with HCC and those paired adjacent normal hepatic tissues was performed by RayBio® human biotin-label-based cytokine antibody arrays, which covered 1000 well-characterised human cytokines
The expression of DcR3, TGFβ3 and TGFβ3 receptor (TGFβRΙ) was upregulated in tumours compared with normal tissues. These data were consistent with the hypothesis that the combination of TGFβ3 and TGFβR regulated DcR3 expression in the HCC microenvironment
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a notably poor prognosis[1]. The extensive expression of cytokines and chemokines is believed to create a microenvironment that favours the development of HCC3. The mechanism governing how cytokines and chemokines. The immune system functions as a host defensive mechanism that protects against tumour development. Patients with tumours exhibit weaker immune surveillance capability and a variety of immune dysregulations, including an imbalance of CD4+ T cells, CD8+ T cells, and associated cytokines[4,5]. Naive CD4+ T cells derived from the thymus differentiate into different subtypes at the periphery in response to antigen stimulation. The first classification divided CD4+ effector cells into two subsets: Th1, characterised by the production and release of interferon gamma (IFN-ɣ), and Th2, characterised by producing and releasing IL-4. It has become evident that more functional subsets of CD4+
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