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Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key drivers in MASLD progression toward HCC. However, it remains unclear whether multiple B cell populations or a distinct B cell subset regulates inflammatory responses during liver disease progression. The scope of this study was to define protumorigenic B cell subsets in MASLD and HCC., Methods: Multicolor flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed to investigate B cell populations locally (in liver tissue) and systemically (in the blood) in mice with MASLD (n = 6) and HCC (n = 5-6). The results obtained in mice were also verified in patients with MASLD (n = 19) and HCC (n = 16)., Results: Our study revealed an increase of two regulatory B cell (Breg) subsets, CD19 + B220 + CD5 + CD1d + ( p <0.0001) and CD19 - B220 + CD5 + CD1d - ( p <0.0001), both of which highly overexpress IgM/IgD, PD-L1, and IL-10, in the livers of mice with MASLD and HCC. Furthermore, we showed that B-cell depletion therapy in combination with a Listeria- based vaccine decreased CD19 - B220 + CD5 + CD1d - Bregs ( p  = 0.0103), and improved survival of mice with HCC. We also found CD19 + CD5 + IL-10 + ( p  = 0.0167), CD19 + CD5 + PD-L1 + ( p  = 0.0333) and CD19 + CD5 + IgM + IgD + ( p  = 0.0317) B cells in human HCCs. In addition, strong overexpression of IgM/IgD, PD-L1, IL-10, were detected on non-switched memory B cells ( p  = 0.0049) and plasmablasts ( p  = 0.0020). The examination of blood samples obtained from patients with MASLD showed an increase of total B cells expressing IL-10 ( p <0.0001) and IgM/IgD ( p  = 0.3361), CD19 + CD20 + CD5 + CD1d + Bregs ( p  = 0.6424) and CD19 + CD20 + CD27 + non-switched memory B cells ( p  = 0.0003)., Conclusions: Our results provide novel insights into the protumorigenic roles of several B cell subsets, the specific targeting of which could abrogate the progression of liver disease., Impact and Implications: Hepatocellular carcinoma (HCC) is the primary liver cancer with a constantly rising mortality rate. Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging important cause of HCC. Current treatment options for HCC are limited and there is a high risk of recurrence. The study aims to identify new therapeutic strategies by exploring the immunological aspects of MASLD and HCC. Our findings extend the current knowledge on the role of B cells in the progression of MASLD and HCC. This study emphasizes the involvement of IgM + IgD + regulatory B cells (Bregs) in malignant liver disease progression. These Bregs characterized by a high expression of PD-L1, IL-10, IgM, and IgD. Two other B cell subsets with immunosuppressive phenotype have been found in the study in murine liver disease - plasmablasts and non-switched memory B cells. Targeting these B cells could lead to more effective treatments of HCC., (© 2024 The Authors.)

In this study, we investigated compounds of plant and mushroom origin belonging to Traditional Chinese Medicine (TCM) and to Traditional Tibetan Medicine (TTM): a sandy beige mushroom Trametes robiniophila Murr, commonly known as Huaier/TCM as well as Ershiwuwei Songshi Wan and Qiwei Honghua Shusheng Wan, which both belong to TTM. We aimed to study the efficacy of TTM and TCM in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in vitro . TCM and TTM were tested either as a monotherapy, or in combination with standard therapeutics: sorafenib for HCC treatment and gemcitabine for CCA. We also discovered a protective mechanism behind the most successful therapeutic combinations. The results demonstrated that TCM and TTM inhibited the proliferation of cancer cells in a time- and dose-dependent manner. The results were compared to classical chemotherapeutics currently used in the clinic: sorafenib for HCC and gemcitabine for CCA. In HCC settings, a combination of Huaier (16 mg/ml) with half of the human plasma concentration of sorafenib, Qiwei Honghua Shusheng Wan (1 mg/ml) monotherapy as well as its combination with half or even a quarter dose of the human plasma concentration of sorafenib represented the most efficient treatments, inhibiting the growth of HCC cells more effectively than the standard therapy. The inhibitory mechanism relied on a strong induction of apoptosis. In CCA settings, Ershiwuwei Songshi Wan and Qiwei Honghua Shusheng Wan as monotherapies or in combination with very low doses of gemcitabine inhibited the growth of CCA cells more efficiently than the standard therapy. Importantly, Ershiwuwei Songshi Wan at the 8 and 16 mg/ml concentrations and Qiwei Honghua Shusheng Wan at the 4 mg/ml concentration were efficacious with gemcitabine applied at massively reduced concentrations. The protective mechanism in CCA relied on a strong induction of early and late apoptosis. Cellular senescence and necroptosis were not associated with protection against HCC/CCA. Combination therapy with TCM or TTM allowed for a dose reduction of standard chemotherapeutics. This is especially important as both chemotherapeutic drugs show strong side effects in patients. The reduction of chemotherapeutics and the synergistic effect observed while applying them in combination with TCM and TTM has strong perspectives for the clinic and patients suffering from HCC and CCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suo, Hochnadel, Petriv, Franke, Schmidt, Limanska, Tugai, Jedicke, Broenstrup, Manns and Yevsa.)

Primary liver cancer (PLC) comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represents the third deadliest cancer worldwide with still insufficient treatment options. We have previously found that CD4 T helper 1 (Th1) response is indispensable for the protection against PLC. In the present research, we aimed to test the potent inducers of Th1 responses, live-attenuated Listeria monocytogenes ∆actA/∆inlB strain as preventive/therapeutic vaccine candidate in liver fibrosis, HCC, and CCA. Studies were performed using autochthonous models of HCC and CCA, highly reflecting human disease. L. monocytogenes ∆actA/∆inlB demonstrated strong safety/efficacy in premalignant and malignant liver diseases. The protective mechanism relied on the induction of strong tumor-specific immune responses that keep the development of hepatobiliary cancers under control. Combination therapy, comprising Listeria vaccination and a checkpoint inhibitor blockade significantly extended the survival of HCC-bearing mice even at the advanced stages of the disease. This is the first report on the safety and efficacy of Listeria-based vaccine in liver fibrosis, as well as the first proof of principle study on Listeria-based vaccines in CCA. Our study paves the way for the use of live-attenuated Listeria as safe and efficient vaccine and a potent inducer of protective immune responses in liver fibrosis and hepatobiliary malignancies., (© 2022. The Author(s).)

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a very poor prognosis and constantly growing incidence. Among other primary risks of HCC, metabolic disorders and obesity have been extensively investigated over recent decades. The latter can promote nonalcoholic fatty liver disease (NAFLD) leading to the inflammatory form of nonalcoholic steatohepatitis (NASH), that, in turn, promotes HCC. Molecular determinants of this pathogenic progression, however, remain largely undefined. In this study, we have focussed on the investigation of α-dicarbonyl compounds (α-dC), highly reactive and tightly associated with overweight-induced metabolic disorders, and studied their potential role in NAFLD and progression toward HCC using murine models. NAFLD was induced using high-fat diet (HFD). Autochthonous HCC was induced using transposon-based stable intrahepatic overexpression of oncogenic NRAS G12V in mice lacking p19 Arf tumor suppressor. Our study demonstrates that the HFD regimen and HCC resulted in strong upregulation of α-dC in the liver, heart, and muscles. In addition, an increase in α-dC was confirmed in sera of NAFLD and NASH patients. Furthermore, higher expression of the receptor for advanced glycation products (RAGE) was detected exclusively on immune cells and not on stroma cells in livers of mice with liver cancer progression. Our work confirms astable interplay of liver inflammation, carbonyl stress mediated by α-dC, and upregulated RAGE expression on CD8 + Tand natural killer (NK) cells in situ in NAFLD and HCC, as key factors/determinants in liver disease progression. The obtained findings underline the role of α-dC and RAGE + CD8 + Tand RAGE + NK cells as biomarkers and candidates for a local therapeutic intervention in NAFLD and malignant liver disease., Competing Interests: The authors report no conflict of interest. H.W. is a consultant by Bayer, Eisai, MSD and Roche, H.W. is a clinical trial investigator by Bayer and Roche., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The innate immune system senses influenza A virus (IAV) through different pathogen-recognition receptors including Toll-like receptor 7 (TLR7). Downstream of viral recognition natural killer (NK) cells are activated as part of the anti-IAV immune response. Despite the known decisive role of TLR7 for NK cell activation by therapeutic immunostimulatory RNAs, the contribution of TLR7 to the NK cell response following IAV infection has not been addressed. We have analyzed lung cytokine responses as well as the activation, interferon (IFN)-γ production, and cytotoxicity of lung and splenic NK cells following sublethal respiratory IAV infection in wild-type and TLR7ko mice. Early airway IFN-γ levels as well as the induction of lung NK cell CD69 expression and IFN-γ production in response to IAV infection were significantly attenuated in TLR7-deficient hosts. Strikingly, respiratory IAV infection also primed splenic NK cells for IFN-γ production, degranulation, and target cell lysis, all of which were fully dependent on TLR7. At the same time, lung type I IFN levels were significantly reduced in TLR7ko mice early following IAV infection, displaying a potential upstream mechanism of the attenuated NK cell activation observed. Taken together, our data clearly demonstrate a specific role for TLR7 signaling in local and systemic NK cell activation following respiratory IAV infection despite the presence of redundant innate IAV-recognition pathways.

Hepatobiliary and pancreatic cancers along with other gastrointestinal malignancies remain the leading cause of cancer-related deaths worldwide. Strategies developed in the recent years on immunotherapy and cancer vaccines in the setting of primary liver cancer as well as in pancreatic cancer are the scope of this review. Significance of orthotopic and autochthonous animal models which mimic and/or closely reflect human malignancies allowing for a prompt and trustworthy analysis of new therapeutics is underlined. Combinational approaches that on one hand, specifically target a defined cancer-driving pathway, and on the other hand, restore the functions of immune cells, which effector functions are often suppressed by a tumor milieu, are shown to have the strongest perspectives and future directions. Among combinational immunotherapeutic approaches a personalized- and individual cancer case-based therapy is of special importance.

Background & Aims: Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication., Methods: We analyzed replication of the subgenomic JFH1 replicon in embryonic fibroblasts and primary hepatocytes from mice with disruptions in genes encoding factors in the IFN-dependent and alternative antiviral pathways (signal transducers and activators of transcription 1 [STAT1], protein kinase R, interferon regulatory factors (IRF) IRF-1, IRF-3, IRF-5, IRF-7, mitochondrial antiviral signaling molecule [MAVS], and IFN receptor [IFNAR]). We also assessed the effects of expression of these factors by mouse primary hepatocytes on HCV replication., Results: In addition to IRF-3- and IFN-mediated antiviral responses, IFN-independent, but IRF-1- and IRF-5-dependent mechanisms, restrict HCV replication in mouse embryonic fibroblasts. In primary hepatocytes these IFN-independent require MAVS and IRF-1., Conclusions: HCV replication is limited by interferon-mediated pathways as well pathways that are independent of type I IFNs. IRF1 and IRF5 control IFN-independent signaling events that lead to antiviral responses. We observed antiviral roles of IRF1 and IRF5 that were IFN-independent and cell-type specific. These mechanisms are important in controlling viruses that interfere with the IFN signaling because cells retain the ability to induce functional but local antiviral states through expression of interferon-stimulated genes., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)