Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.

Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatic inflammation and damage. The pathogenesis of chronic hepatitis B (CHB) infection is predominantly mediated by persistent intrahepatic immunopathology. With the characterization of unique anatomical and immunological structure, the liver is also deemed an immunological organ, which gives rise to massive cytokines and chemokines under pathogenesis conditions, having significant implications for the progression of HBV infection. The intrahepatic innate immune system is responsible for the formidable source of cytokines and chemokines, with the latter also derived from hepatic parenchymal cells. In addition, systemic cytokines and chemokines are disturbed along with the disease course. Since HBV is a stealth virus, persistent exposure to HBV-related antigens confers to immune exhaustion, whereby regulatory cells are recruited by intrahepatic chemokines and cytokines, including interleukin-10 and transforming growth factor β, are involved in such series of causal events. Although the considerable value of two types of available approved treatment, interferons and nucleos(t)ide analogues, effectively suppress HBV replication, neither of them is sufficient for optimal restoration of the immunological attrition state to win the battle of the functional or virological cure of CHB infection. Notably, cytokines and chemokines play a crucial role in regulating the immune response. They exert effects by directly acting on HBV or indirectly manipulating target immune cells. As such, specific cytokines and chemokines, with a potential possibility to serve as novel immunological interventions, combined with those that target the virus itself, seem to be promising prospects in curative CHB infection. Here, we systematically review the recent literature that elucidates cytokine and chemokine-mediated pathogenesis and immune exhaustion of HBV infection and their dynamics triggered by current mainstream anti-HBV therapy. The predictive value of disease progression or control and the immunotherapies target of specific major cytokines and chemokines in CHB infection will also be delineated.

The serological hallmark of primary biliary cirrhosis (PBC) is the presence of high titer and specific antimitochondrial antibodies (AMAs). Although there is no global immune defect in patients with PBC, there is widespread dysregulated B‐cell function, including increased sera levels of immunoglobulin M and enhanced B‐cell responses to cytosine‐phosphate‐guanine stimulation. The mechanisms involved in this B‐cell dysfunction have remained unknown. To address this issue, we focused on identifying the frequencies of B‐cell subsets in patients with PBC and the mechanisms that lead to B‐cell dysregulation, including the relationships with chemokine (C‐X‐C motif) receptor 5 (CXCR5)⁺CD4⁺T cells. Herein, we report that elevations of both serum and intrahepatic interleukin‐21 (IL‐21) were found in patients with PBC and, in particular, promoted B‐cell proliferation, signal transducer and activator of transcription 3 phosphorylation and AMA production in vitro. More important, upon stimulation with recombinant E2 subunit of pyruvate dehydrogenase complex, CXCR5⁺CD4⁺T cells in PBC produced higher levels of IL‐21 than healthy controls. Additionally, sorted CXCR5⁺CD4⁺T cells increased production of AMAs by autologous CD19⁺B cells. Indeed, elevated expression of intrahepatic chemokine (C‐X‐C motif) ligand 13 (CXCL13), a key chemokine of CXCR5⁺ cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4⁺, CXCR5⁺, CD19⁺, and CD38⁺ cells. Conclusion: CXCL13 promotes aggregation of CD19⁺B cells and CXCR5⁺CD4⁺T cells, which directs the aberrant AMA response by IL‐21. These data have implications for potential immunotherapy and also reflect the unique lymphoid biology in liver of PBC. (Hepatology 2015;61:1998‐2007)

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γ_c) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

Strategies that target functional recovery of exhausted hepatitis B virus (HBV)-specific CD8 ⁺ T cells are beneficial for viral control, but the potential for interleukin (IL)-21 to rescue CD8 ⁺ T cell function is not well understood. We investigated the effect of IL-21 on CD8⁺ T cell responses by phenotypic and functional analysis of samples from patients with chronic HBV infection and mouse model with HBV expression. IL-21 promoted the proliferative capacity of HBV-specific CD8⁺ T cells and downregulated expression of inhibitory receptors programmed death-1 and T cell immunoglobulin domain and mucin domain 3. Additionally, IL-21 boosted the production of interferon-γ, granzyme B, and CD107a in HBV-specific CD8⁺ T cells and enhanced the cytolytic activity of CD8⁺ T cells against HepG2.2.15 cells. Notably, an HBV mouse model established from IL-21 receptor knockout mice showed significantly decreased frequency of HBV-specific CD8⁺ T cells and increased levels of serum HBsAg. Meanwhile, administration of recombinant mouse IL-21 in an HBV mouse model established from wild-type mice resulted in enhanced functionality of HBV-specific CD8⁺ T cells and accelerated HBsAg clearance. IL-21 enhances the antiviral effect of HBV-specific CD8⁺ T cells, suggesting that it may contribute to viral clearance in chronic HBV infection.