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It is well established that humoral immunity targeting hepatitis B virus surface antigen (HBsAg) plays a critical role in viral clearance and clinical cure. However, the functional changes in HBsAg-specific B cells before and after achieving functional cure remain poorly understood. In this study, we characterized circulating HBsAg-specific B cells and identified functional shifts and B-cell epitopes directly associated with HBsAg loss. The phenotypes and functions of HBV-specific B cells in patients with chronic HBV infection were investigated using a dual staining method and the ELISpot assay. Epitope mapping was performed to identify B cell epitopes associated with functional cure. Hyperactivated HBsAg-specific B cells in patients who achieved HBsAg loss were composed of enriched resting memory and contracted atypical memory fractions, accompanied by sustained co-expression of multiple inhibitory receptors and increased IL-6 secretion. The frequency of HBsAb-secreting B cells was significantly increased after achieving a functional cure. The rHBsAg displayed a weaker immunomodulatory effect on B cells than rHBeAg and rHBcAg in vitro. Notably, sera from patients with HBsAg loss reacted mainly with peptides S60, S61, and S76, suggesting that these are dominant linear B-cell epitopes relevant for functional cure. Intriguingly, patients reactive with S76 showed a higher frequency of the HLA class II DQB1*05:01 allele. Taken together, HBsAg-specific B cells were partially restored in patients after achieving a functional cure. Functional cure-related epitopes may be promising targets for developing therapeutic vaccines to treat HBV infection and promote functional cure.

Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer. IL-21 regulates both innate and adaptive immune responses and has key roles in antitumor and antiviral responses. However, the role of IL-21 in HCC development is poorly defined. In the current study, we explored the role of IL-21R signaling in HCC growth by using IL-21R knockout mice and HCC mouse models. We discovered that IL-21R signaling deficiency promoted HCC growth in tumor-bearing mice. We showed that IL-21R deletion reduced T cells infiltration and activation as well as their function but increased the accumulation of myeloid-derived suppressor cells in tumor tissues to enhance HCC growth. Furthermore, loss of IL-21R signaling in tumor-bearing mice resulted in an imbalance of the systemic immune system characterized by decreased antitumor immune cells and increased immunosuppressive cells in the spleen and lymph nodes. In addition, we revealed that IL-21R signaling is critical for the expansion of antitumor immune cells in the memory immune response to tumor rechallenge. Finally, we showed that the transcriptional levels of IL-21 in the peritumoral region and IL-21R within the tumor are associated with survival and recurrence of HCC patients. In conclusion, our study demonstrates that IL-21R signaling is essential for controlling the development of HCC and immunological memory response to tumor challenge.