BACKGROUND & AIMS:The function and quantity of CD8+ T-cell responses is superior in acute vs. chronic HBV infection. However, whether different HBV-derived epitopes are targeted in these distinct courses of HBV infection remains unclear. METHODS:We screened peripheral blood mononuclear cells from 56 patients with chronic HBV infection genotype D and 32 patients with acute/resolved HBV infection to identify responses to overlapping peptides (18mers) covering the full HBV genotype D proteome. We then performed experimental fine-mapping of the minimal optimal epitopes. RESULTS:Patients with acute HBV infection showed a broad HBV-specific CD8+ T-cell epitope repertoire. After spontaneous resolution, the strength of HBV-specific CD8 T-cell responses decreased, whereas the broad epitope landscape was preserved. In chronic HBV infection, the specificity of HBV-specific CD8+ T-cell responses to HBV antigens was shifted, with a lack of functional HBsAg-specific CD8+ T-cell responses (p = 0.0007), as recently described. Interestingly, patients with chronic HBV infection showed significantly more HLA-B-restricted HBV-specific CD8+ T-cell responses than HLA-A-restricted responses (33 vs. 19), whereas this distribution was balanced in patients with acute/resolved HBV infection (16 vs. 27; p = 0.0364). Most (79.6%) of the detected responses showed conserved autologous viral sequences. This observation was confirmed in a broader sequence dataset with no evidence for HLA-B-driven CD8+ T-cell selection pressure. CONCLUSIONS:In contrast to acute/resolved infection, conserved HLA-B-restricted epitopes are dominant in chronic HBV infection, making them interesting candidates for immunotherapeutic approaches towards functional cure of chronic HBV infection. IMPACT AND IMPLICATIONS:To date, there is no treatment to achieve functional cure of chronic HBV infection. Immunotherapy boosting dysfunctional HBV-specific CD8+ T cells is an interesting approach, but relies on selection of optimal target epitopes. Using an unbiased approach, we found that the HBV-specific CD8+ T-cell epitope repertoire in chronic HBV infection is not well covered by previously described epitopes. We characterized 28 novel, primarily HLA-B-restricted epitopes that are dominantly targeted in chronic HBV infection. These might be used as a "toolbox" for immunological studies and immunotherapeutic approaches.

The liver is a highly multifunctional organ that can perform many metabolic and immunological functions due to a highly complex spatially organised microarchitecture that is disturbed in many liver diseases. Recent methodological advances in spatial omics technologies enable the comprehensive study of the intrahepatic proteome, transcriptome and metabolome at near single-cell and subcellular resolution. The spatial resolution adds an additional dimension to our understanding of the liver, with the potential to revolutionise our insights into the cellular and molecular mechanisms underlying liver physiology and their dysregulation in liver disease. The identification of spatial niches and interactions is empowered by advanced bioinformatics approaches facilitating spatial cellular and network-level analysis and providing novel opportunities for clinical translation. A recent example in immuno-oncology is the use of spatial architecture-based immune classifications, which can improve patient stratification. In this review, we provide an overview of the current methodology and novel spatial insights into metabolic, infectious, immune-mediated, toxic and malign liver diseases and discuss perspectives for clinical translation.

B cells are highly abundant lymphocytes and central players in humoral immunity. Although T cells are well known to support humoral responses, how B cells influence T cell responses is less understood. Here, we show that B cells are critical for CD8+ T cell responses to chronic, but not acute, viral infections. In the absence of B cells, T cells responding to chronic infection exhibited severely impaired effector differentiation. This dependency on B cell help was dictated by high antigen loads and strong T cell receptor (TCR) stimulation. Loss of either B cells or interferon-I (IFN-I) signaling led to severe functional deficits in exhausted T cells, implicating B cells as key producers of IFN-I. The IFN-I-dependent T cell response to strong TCR stimulation is mediated, in part, by the transcription factor IRF1. Therefore, during chronic infection, we uncover an important role for B cell-derived IFN-I in modulating T cell responses to strong TCR stimulation.

BACKGROUND:Despite the proven superiority against sorafenib, atezolizumab plus bevacizumab (A+B) lacks long-term efficacy data in unresectable hepatocellular carcinoma (uHCC). This study assessed clinicopathologic factors associated with long-term survival with A+B. METHODS:We analyzed patients receiving first-line A+B within AB-Real, a large multicenter registry across Europe, Asia, and the USA. Long-term survivors (LTS) were defined as patients surviving at 24 months. Landmark survival outcomes and associations between baseline clinicopathologic factors and overall survival (OS) were evaluated. RESULTS:Of 1346 patients enrolled, 1085 with Child-Pugh A and ECOG 0-1 received first-line A+B. The median OS was 19.2 months (95% CI: 17.6-20.9), and 2- and 3-year survival rates were 41.4% and 29.3%. Among 695 patients with adequate follow-up, 190 were classified as LTS. The overall response rate was 24.7%, and long-term survivorship was significantly enhanced in radiologic responders (52.2% vs 8.8%, p < 0.001). Compared to non-LTS, LTS more frequently had ALBI grade 1 liver reserve (64.6% vs 38.5%), less PVI (17.9% vs 36.4%), smaller maximum tumor size (3.8 vs 7.0 cm), and lower AFP (median 23.0 vs 240.8 ng/mL) (all p < 0.001). Notably, nearly half (48.8%) of radiologic responders who did not achieve long-term survival had ≥ 2 adverse baseline features, underscoring that tumor burden and liver reserve remain prognostically relevant even among responders. CONCLUSIONS:AB-Real provides the first global real-world evidence of long-term efficacy of A+B in uHCC. Long-term survivorship is enhanced in radiological responders and strongly associated with pre-treatment tumor factors and liver function.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome in patients with decompensated cirrhosis and is characterized by acute failure of one or more organ systems. Despite advances in clinical management, ACLF continues to be associated with high short-term mortality.This article provides an up-to-date, guideline-based overview of the classification, diagnosis, and therapeutic approaches to ACLF, drawing on the latest literature and consensus definitions.ACLF is defined by acute decompensation of cirrhosis accompanied by failure of the liver and/or other organs including the kidneys, cardiovascular system, lungs, central nervous system, and coagulation. The EASL-CLIF Consortium criteria distinguish three grades of ACLF based on the number and type of organ failures; increasing grade correlates with sharply rising short- and medium-term mortality. Pathophysiologically, ACLF is characterized by an overwhelming systemic inflammatory response typically triggered by bacterial infections, severe alcoholic hepatitis, or gastrointestinal bleeding. Prognostication is guided by CLIF-C OF, CLIF-C ACLF, and CLIF-C AD scores, which can also help to identify patients at high risk for further decompensation. Management focuses on rapid identification and reversal of precipitating factors, organ support, and early evaluation for liver transplantation, as it remains the sole curative option in non-reversible ACLF. Preemptive TIPS placement is reserved for selected cases, with individualized risk assessment being critical due to the increased complication rate in severe multiorgan failure.ACLF remains the most severe complication of cirrhosis, marked by high short-term mortality. Early, guideline-based interventions and multidisciplinary management can improve outcomes. Accurate risk stratification and timely consideration of liver transplantation are essential to enhance patient survival.

Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) has become an established interventional procedure for treating decompensated liver cirrhosis and its complications, such as portal hypertension. Current research focuses on optimizing patient selection and timing to enhance outcomes further. TIPS effectively reduces portal vein pressure, mitigating bacterial translocation and systemic inflammation associated with cirrhosis. This reduction in inflammation has been shown to decrease decompensation events and improve survival rates. However, challenges remain regarding the precise adjustment of the portosystemic gradient (PSG) to balance symptom control with minimizing risks such as hepatic encephalopathy or cardiac complications. The main indications for TIPS include variceal bleeding (especially high-risk patients requiring preemptive TIPS within 72 hours), recurrent ascites, and Budd-Chiari syndrome. Strict patient selection is crucial to maximize benefits while minimizing risks. Emerging evidence highlights the importance of addressing both portal hypertension and inflammation to improve clinical outcomes. In summary, TIPS represents an effective approach to managing complications of liver cirrhosis that improves survival and quality of life for affected patients.

BACKGROUND:Combination immune checkpoint inhibitors are recommended as first-line therapy for advanced hepatocellular carcinoma. However, only a third of patients respond to treatment, and improved approaches to predict response are required. Using baseline clinical data, we aimed to use advanced machine learning models to predict overall survival and progression-free survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab. METHODS:This retrospective cohort study was conducted at 24 centres across eight countries. Patients aged 18 years and older with a histological or radiological diagnosis of advanced hepatocellular carcinoma were included; those who had received previous systemic therapy for hepatocellular carcinoma were excluded. All patients received intravenous atezolizumab 1200 mg plus bevacizumab 15 mg/kg once every 3 weeks until disease progression. Seven supervised machine learning models, in combination with 13 feature selection techniques, were trained on 44 baseline clinical variables for the prediction of overall survival and progression-free survival. The three best-performing models, combined with their optimum feature selection techniques, were used to develop ensemble machine learning models for the prediction of overall survival and progression-free survival. The primary outcomes of the study were the predictions of overall survival, progression-free survival, and immunotherapy response using advanced machine learning. k-means clustering was used to stratify patients into two groups: those at low risk and those at high risk of either death (in the overall survival model) or disease progression (in the progression-free survival model). FINDINGS:934 patients who received immunotherapy from May 1, 2018 and were followed up until Oct 1, 2023 were screened, of whom 160 were excluded and 774 were included in the final study. Patients were divided into training (n=339), internal validation (n=146) and external validation (n=289) cohorts. Support vector machine, neural network, and naive Bayes algorithms had the best performance in the prediction of overall survival; for progression-free survival, the highest-performing algorithms were ridge regression, naive Bayes, and logistic regression. In the external validation cohort, the ensemble model for the prediction of overall survival (area under the receiver operating characteristic curve 0·75 [95% CI 0·69-0·81]) significantly outperformed all eight of the tested clinical benchmark variables: Barcelona Clinic Liver Cancer (BCLC) stage (0·54 [0·48-0·61]; p<0·0001), α-fetoprotein (AFP) concentration (0·60 [0·54-0·67]; p=0·0007), albumin-bilirubin (ALBI) grade (0·64 [0·58-0·71]; p=0·0003), neutrophil-to-lymphocyte ratio (0·56 [0·49-0·62]; p<0·0001), platelet-to-lymphocyte ratio (0·51 [0·44-0·58]; p<0·0001), combined ALBI grade and BCLC stage (0·67 [0·60-0·73]; p=0·0074), and two BCLC subclassifications (0·62 [0·55-0·69]; p=0·0007 and 0·61 [0·55-0·68]; p=0·0018). The ensemble model for the prediction of progression-free survival (0·64 [0·59-0·70]) outperformed five of the eight clinical predictors: BCLC stage (0·52 [0·46-0·58]; p<0·0001), neutrophil-to-lymphocyte ratio (0·53 [0·47-0·59]; p=0·0069), platelet-to-lymphocyte ratio (0·54 [0·48-0·60]; p=0·016), and two BCLC subclassifications (0·57 [0·50-0·64]; p=0·020 and 0·55 [0·49-0·62]; p=0·0091); the model did not outperform AFP concentration (0·59 [0·53-0·64]; p=0·14), ALBI grade (0·62 [0·56-0·67]; p=0·44), or combined ALBI grade and BCLC stage (0·59 [0·53-0·66]; p=0·12). For the overall survival model, patients stratified into the low-risk group had significantly longer median overall survival (16·4 months [95% CI 14·2-21·6]) than those in the high-risk group (4·8 months [3·0-6·9]; p<0·0001); similarly, patients stratified by the progression-free survival model into the low-risk group had significantly longer median progression-free survival (8·9 months [7·3-11·1]) than those in the high-risk group (3·7 months [2·9-5·6]; p=0·0021). INTERPRETATION:Our advanced machine learning models, which use routinely collected baseline clinical variables, are robust and externally validated and outperform established clinical biomarkers for predicting clinical outcomes with atezolizumab plus bevacizumab. These data-driven models could be used to stratify patients with hepatocellular carcinoma for personalised treatment strategies. FUNDING:None.

Chronic HBV infection remains a major global health burden, with current antiviral therapies effectively suppressing viral replication but rarely achieving functional cure. Adaptive immunity is central to viral clearance but is profoundly impaired during chronic infection. Inducing and enhancing adaptive immunity through therapeutic vaccines, immune checkpoint inhibitors or T cell-based therapies represents a promising approach for HBV cure strategies. However, recent preclinical and clinical studies have demonstrated only limited efficacy, underscoring major immunological challenges. In this review, we summarise current knowledge of the correlates of viral clearance and persistence, discuss key unresolved questions and outline future research directions needed to advance immune-based HBV cure strategies.

γδ T cells maintain intestinal immune homeostasis, but their contributions to human ulcerative colitis (UC) are poorly understood. We characterized γδ T cells in intestinal biopsies obtained from patients with UC and healthy donors using single-cell RNA sequencing, T cell receptor profiling, and mass cytometry. UC reduced CD103 + Vγ4Vδ1 + γδ intraepithelial lymphocytes (γδ IELs) and increased γδ T cell subsets with stemlike phenotypes expressing TCF-1 (T cell factor 1) and PD-1 (programmed cell death receptor 1) or effector-like phenotypes expressing granzyme B, perforin, and T-bet in the lamina propria. γδ T cell composition changes in UC correlated with decreased expression of epithelial BTNL3 and BTNL8 and increased BTN3A1 and BTN3A3 , suggesting altered recruitment and activation. Clinical improvement recovered γδ IELs and reduced inflammation-associated subsets. Inflammation-associated changes were observed in peripheral blood γδ T cells. Thus, distinct γδ T cell subsets in different niches exert protective or pathogenic functions in UC.

The transition from compensated to decompensated advanced chronic liver disease (ACLD) is associated with increased mortality. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mmHg, is the main precondition of decompensation. Non-invasive tools like transient elastography help identifying patients at risk. Preventing the first decompensation, especially ascites, is a key therapeutic goal. Non-selective beta-blockers (NSBBs), particularly carvedilol, reduce portal pressure and have shown efficacy in preventing decompensation, independent of variceal status. Lifestyle modification and treating underlying liver disease (e.g., alcohol abstinence, viral eradication) remain essential. Early identification and initiation of therapy in CSPH can change the natural history of cirrhosis and improve patient outcomes.

Intrahepatic immune responses are often insufficient to control hepatitis virus infections. A recent study by Venzin and colleagues demonstrates a detailed mechanism by which an intrahepatic tricellular network and the cytokine IL-27 can augment virus-specific immunity.

Hepatitis C virus (HCV) exists as a heterogenous quasispecies, but the phenotypic consequences of viral variability are widely unexplored. Here we identify a replication enhancing domain (ReED) in non-structural protein 5A conferring high replication fitness to clinical isolates. Accumulation of mutations in the ReED mediates high genome replication capacity. In a cohort of liver transplant patients, high replicator variants are exclusively found in individuals with severe disease outcome, suggesting that high viral replication fitness is associated with increased viral pathogenesis. Analysis of large sequence cohorts reveals that overall only 10% of viral genomes show genetic signatures of high replicators, which are enriched in recipients of liver transplantations, patients developing hepatocellular carcinoma and in HIV coinfected individuals. Overall, our data suggests that low replication fitness is a hallmark of HCV, contributing to establishment of persistence, whereas high replicators appear to have an advantage under conditions of immune suppression, thereby enforcing pathogenesis.