Expansion of effector regulatory T cells in steroid responders of severe alcohol-associated hepatitis.

While steroid therapy is the preferred treatment for severe alcohol-associated hepatitis, the role of effector regulatory T (eTreg) cells and their association with steroid response and clinical outcomes in these patients remains to be elucidated. We prospectively enrolled 47 consecutive patients with alcohol-associated hepatitis, consisting of severe alcohol-associated hepatitis treated with steroids (n=18; steroid-treated group) and mild alcohol-associated hepatitis (n=29; nontreated group). After isolating peripheral blood mononuclear cells from the patients at enrollment and again 7 days later, the frequency of eTreg cells was examined using flow cytometry. Single-cell RNA sequencing analysis was conducted using paired peripheral blood mononuclear cells. In vitro experiments were also performed to assess phenotype changes and the suppressive function of Treg cells following steroid treatment. The steroid-treated group exhibited significantly higher Model for End-Stage Liver Disease scores than the nontreated group ( p < 0.01). Within the steroid-treated group, the proportion of eTreg cells significantly expanded in the steroid responders (n=13; p = 0.01). Furthermore, a significant positive correlation was observed between the decrease in the Model for End-Stage Liver Disease score and the increase in eTreg cells ( p < 0.05). Single-cell RNA sequencing using paired peripheral blood mononuclear cells (pre-steroid and post-steroid therapy) from a steroid responder revealed gene expression changes in T cells and monocytes, suggesting enhancement of Treg cell function. In vitro results showed an elevation in the proportion of eTreg cells after steroid therapy. In conclusion, our findings suggest that the efficacy of steroid therapy in patients with severe alcohol-associated hepatitis is mediated by an increase in the number of eTreg cells.

Differential HBV replicative markers and covalently closed circular DNA transcription in immune-active chronic hepatitis B with and without HBeAg.

BACKGROUND AND AIMS: Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. METHODS: This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed. RESULTS: Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients. CONCLUSIONS: HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patient with chronic hepatitis B.

BACKGROUND AND AIM: Our study evaluated the outcomes of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). We assessed viral and biochemical responses as well as changes in the estimated glomerular filtration rate (eGFR) and bone mineral density (BMD). METHODS: This retrospective multicenter study included CHB patients who achieved virologic response (VR) (HBV DNA < 20 IU/mL) while on TDF and were subsequently switched to TAF between April 2018 and October 2021. RESULTS: This study included 309 patients with a median age of 59 years, and 42.1% were male. The mean duration of TDF and TAF administration were 54.0 and 37.5 months, respectively. All patients maintained VR after switching to TAF. Alanine aminotransferase (ALT) normalization rate significantly increased 6 months after switching (74.8%-83.5%; P = 0.008). Adjusted eGFR significantly improved at 6 months (+5.55 ± 10.52 mL/min/1.73 m2; P < 0.001) and 12 months (+6.02 ± 10.70 mL/min/1.73 m2; P < 0.001) after switching. In the subgroup of patients with renal impairment (eGFR < 60 mL/min/1.73 m2), significant improvement in renal function was observed at 6 months (+0.6 ± 10.5 mL/min/1.73 m2; P < 0.001) and 12 months (+1.0 ± 10.7 mL/min/1.73 m2; P < 0.001) after switching to TAF. In patients with osteoporosis (n = 182), switching to TAF resulted in significant improvement in spine and hip BMD at 12 months, with increases of 9.7% (95% CI: 7.0-12.5) and 9.4% (95% CI: 7.0-11.8), respectively. CONCLUSION: In this real-world study, switching to TAF was effective and safe in patients, with notable improvements in ALT levels, renal function, and BMD.

An Immunological Perspective on the Mechanism of Drug Induced Liver Injury: Focused on Drugs for Treatment of Hepatocellular Carcinoma and Liver Transplantation.

The liver is frequently exposed to potentially toxic materials, and it is the primary site of clearance of foreign agents, along with many innate and adaptive immune cells. Subsequently, drug induced liver injury (DILI), which is caused by medications, herbs, and dietary supplements, often occurs and has become an important issue in liver diseases. Reactive metabolites or drug-protein complexes induce DILI via the activation of various innate and adaptive immune cells. There has been a revolutionary development of treatment drugs for hepatocellular carcinoma (HCC) and liver transplantation (LT), including immune checkpoint inhibitors (ICIs), that show high efficacy in patients with advanced HCC. Along with the high efficacy of novel drugs, DILI has become a pivotal issue in the use of new drugs, including ICIs. This review demonstrates the immunological mechanism of DILI, including the innate and adaptive immune systems. Moreover, it aims to provide drug treatment targets, describe the mechanisms of DILI, and detail the management of DILI caused by drugs for HCC and LT.

FK506 and Lactobacillus acidophilus ameliorate acute graft-versus-host disease by modulating the T helper 17/regulatory T-cell balance.

BACKGROUND: Graft-versus-host disease (GvHD) is a critical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The immunosuppressants given to patients undergoing allogeneic HSCT disturb the microbiome and the host immune system, potentially leading to dysbiosis and inflammation, and may affect immune function and bone marrow transplantation. The intestinal microbiome is a target for the development of novel therapies for GvHD. Lactobacillus species are widely used supplements to induce production of antimicrobial and anti-inflammatory factors. METHODS: We determined the effect of the combination of Lactobacillus acidophilus and FK506 on GvHD following major histocompatibility complex-mismatched bone marrow transplantation. RESULTS: The combination treatment suppressed IFN-γ and IL-17-producing T cell differentiation, but increased Foxp3+Treg differentiation and IL-10 production. Also, the combination treatment and combination treated-induced Treg cells modulated the proliferation of murine alloreactive T cells in vitro. Additionally, the combination treatment upregulated Treg-related genes-Nt5e, Foxp3, Ikzf2, Nrp1 and Itgb8-in murine CD4+-T cells. The combination treatment also alleviated GvHD clinically and histopathologically by controlling the effector T cell and Treg balance in vivo. Moreover, the combination treatment decreased Th17 differentiation significantly and significantly upregulated Foxp3 and IL-10 expression in peripheral blood mononuclear cells from healthy controls and liver transplantation (LT) patients. CONCLUSIONS: Therefore, the combination of L. acidophilus and FK506 is effective and safe for patients undergoing allogeneic hematopoietic stem cell transplantation.

Reactivation of Resolved Hepatitis B After Daratumumab for Multiple Myeloma.

The risk of reactivation of resolved hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-negative multiple myeloma patients after daratumumab has not been reported. Among 93 patients with daratumumab treatment, reactivation occurred in 6 patients (6.5%) with one hepatic failure. This is the first report demonstrating a considerable risk of reactivation of resolved HBV after daratumumab.

Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B.

BACKGROUND & AIMS: Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. METHODS: A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post-treatment and defined as achieving both <2000 IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000 IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. RESULTS: The median follow-up period was 7.2 years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P < .001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P = .01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. CONCLUSIONS: During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.

Use of M2BPGi in HCC patients with TACE.

BACKGROUND AND AIM: Serum Mac-2-binding protein glycosylation isomer (M2BPGi) has been studied as a marker for liver fibrosis or cirrhosis. This study explores the potential role of M2BPGi in predicting clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). METHODS: A total of 226 HCC patients undergoing TACE were enrolled. Serum M2BPGi was measured at baseline. Receiver operating characteristic curve analysis was used to determine the cut-off value (= 2.82) of M2BPGi for prediction of patient outcomes. The prognostic performance of M2BPGi was compared with the hepatoma arterial embolization prognostic (HAP) score. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), radiologic response, and recurrence after complete response (CR). RESULTS: Median PFS was 14.5 months. Patients with low M2BPGi levels had significantly better OS and PFS than those with high M2BPGi levels. M2BPGi was an independent variable for PFS and OS. Patients were classified into three groups by combination of M2BPGi and the HAP score. The low-risk group had significantly better PFS and OS than the high-risk and intermediate-risk groups, whereas the differences between the high-risk and intermediate-risk groups were insignificant. The combination showed higher area under the receiver operating characteristic curve for 3-year PFS and OS than the HAP score alone. M2BPGi was a significant predictor of HCC recurrence after achieving CR. CONCLUSIONS: Serum M2BPGi level is a useful prognostic indicator of PFS and OS in TACE-treated HCC patients, as well as recurrent cases, which cannot be predicted with the HAP score. The combination of M2BPGi and the HAP score enhances the detection of TACE-preferred patients.

Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70-80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.

Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma.

Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3' end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.

Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma.

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.

HMGB1/RAGE induces IL-17 expression to exaggerate inflammation in peripheral blood cells of hepatitis B patients.

BACKGROUND: Hepatitis B (HB) is an infectious disease with unfavorable consequence for patients and involved in chronic inflammation of liver. The present study aimed to investigate whether High-mobility group protein B (HMGB)1/receptor for advanced glycation end products (RAGE) aggravates inflammation enhancing the expression of interleukin (IL)-17. METHODS: Mild and severe HB liver tissue and peripheral blood samples were obtained intra-operatively. Histological analysis of the livers was performed by immunohistochemistry. IL-1ß and IL-6 of liver tissue were detected by confocal microscopy staining. Relative mRNA expression was measured by real-time PCR and protein levels were measured by enzyme-linked immunosorbent assay. RESULTS: HMGB1, RAGE and IL-17 expression is increased in liver of HB patients with acute on chronic liver failure (ACLF) compared to healthy controls. HMGB1 treatment induced inflammatory cytokines including IL-17 in peripheral blood cells of HB patients. IL-17 also induced the expression of RAGE and IL-1ß in peripheral blood cells of HB patients with ACLF. On the other hands, the inhibitory factor of p38 and nuclear factor-kappa B reduced the expression of RAGE and IL-1ß in peripheral blood cells HB patients with ACLF. CONCLUSIONS: HMGB1, RAGE and IL-17 expression is increased in liver of severe HB patients. HMGB1 and RAGE interaction may contribute to the inflammation of liver enhancing the expression of IL-17, which can be possibly restored through the decline of the HMGB1/RAGE axis.

Heavy smoking increases early mortality risk in patients with hepatocellular carcinoma after curative treatment.

BACKGROUNDS/AIMS: Although cigarette smoking has been associated with an increased risk of hepatocellular carcinoma (HCC), its association with HCC mortality remains underexplored. We aimed to evaluate the effect of smoking on early mortality in HCC patients following curative treatment. METHODS: Data from the Korean Primary Liver Cancer Registry were examined for HCC patients who underwent liver resection or radiofrequency ablation between 2015 and 2018. Smoking cumulative dose was assessed in pack-years. The primary outcome was the 3-year overall survival (OS). RESULTS: Among 1,924 patients, 161 were classified as heavy smokers (≥40 pack-years). Heavy smokers exhibited a lower 3-year survival rate (77.1%) than nonsmokers (83.3%), with a significant difference observed in the 3-year OS (P=0.016). The assessment of smoking pack-years in relation to 3-year OS revealed a dose-dependent pattern, with the hazard ratio exceeding 1.0 at 20 pack-years and continuing to rise until 40 pack-years, reaching peak at 1.21 (95% confidence interval, 1.01-1.45). Multivariate Cox-regression analysis revealed heavy smoking, age ≥60 years, underlying cirrhosis, tumor size >3 cm, vascular invasion, and Child-Pugh class B/C as risk factors for 3-year OS. Subgroup analyses of patients with a tumor size <3 cm, absence of vascular invasion, and meeting the Milan criteria also showed inferior outcomes for heavy smokers in all three subgroups. CONCLUSIONS: Heavy smoking, defined as a history of >40 pack-years, was linked to poorer 3-year survival outcomes in HCC patients undergoing curative treatments, underscoring the importance of smoking cessation in this population.

An Early Increase in IL-10 and TNF-α Levels Following Atezolizumab Plus Bevacizumab Treatment Predicts Survival in Advanced Hepatocellular Carcinoma Patients: A Prospective Cohort Study.

Background/Objectives: Reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev) are still lacking. Cytokines, which play a crucial role in immune regulation and HCC progression, have potential as predictive markers, but data supporting their use are limited. This study aimed to evaluate the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. Methods: We prospectively enrolled 32 advanced HCC patients, collecting blood samples before the first and second Ate/Bev treatments. These samples were analyzed for IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels to assess changes post-treatment. The primary outcome was overall survival, with a secondary focus on progression-free survival (PFS) at 6 months. Results: The mean age of the participants was 64.2 years, with the majority being male (93.8%). Patients showing increased IL-10, IL-17, and TNF-α levels had significantly better survival (p < 0.05) and marginally improved PFS compared to those with decreased cytokine levels. Interestingly, a positive correlation was noted between changes in IL-10 and TNF-α levels (p = 0.009). Furthermore, a multivariable analysis revealed that increased levels of IL-10 and TNF-α were significant predictors of enhanced survival (hazard ratio, 0.07; 95% confidence interval, 0.01-0.46; p = 0.005). Conclusions: An early increases in IL-10 and TNF-α after Ate/Bev treatment may serve as effective biomarkers for clinical outcomes in advanced HCC patients.

Long-Term HBsAg Titer Kinetics with Entecavir/Tenofovir: Implications for Predicting Functional Cure and Low Levels.

The long-term kinetics of quantitative HBsAg levels in HBV-infected patients treated with entecavir or tenofovir, as well as the role of quantitative HBsAg in predicting functional cure (HBsAg loss) and low HBsAg levels (<2 log IU/mL) remain unclear. Of some 1661 consecutively enrolled patients newly treated with entecavir or tenofovir, we analyzed 852 patients who underwent serial HBsAg level checks every 6-12 months. The primary outcomes included long-term kinetics in HBsAg levels and the rate of functional cure and achieving low HBsAg levels. Over a mean 6.3-year follow-up, the functional cure rate was 2.28% (n = 19), and 12.9% (n = 108) achieved low HBsAg levels. A significant HBsAg level reduction was seen in the first treatment year (p < 0.05), with another stepwise decrease between year 6-7. These trends were pronounced in patients with chronic hepatitis and HBeAg-positivity compared to those with cirrhosis and HBeAg-negativity, respectively. Baseline HBsAg of ≤3 log IU/mL and the first-year HBsAg reduction were key predictors for both functional cure and low HBsAg levels (p < 0.05). In conclusion, our findings elucidate the stepwise reduction in quantitative HBsAg dynamics during high-potency NA therapy (entecavir or tenofovir) along with variations based on different conditions. We also underscore the significance of quantitative HBsAg titer in predicting functional cure and low-HBsAg levels.

Optimal tacrolimus levels for reducing CKD risk and the impact of intrapatient variability on CKD and ESRD development following liver transplantation.

Background/Aims: This study aimed to identify the risk factors for chronic kidney disease (CKD) and end-stage renal disease (ESRD) following liver transplantation (LT), with a specific focus on tacrolimus levels and intrapatient variability (IPV). Methods: Among the 1,076 patients who underwent LT between 2000 and 2018, 952 were included in the analysis. The tacrolimus doses and levels were recorded every 3 months, and the IPV was calculated using the coefficient of variability. The cumulative incidence rates of CKD and ESRD were calculated based on baseline kidney function at the time of LT. The impact of tacrolimus levels and their IPV on the development of CKD and ESRD was evaluated, and the significant risk factors were identified. Results: Within a median follow-up of 97.3 months, the 5-year cumulative incidence rates of CKD (0.58 vs. 0.24) and ESRD (0.07 vs. 0.01) were significantly higher in the acute kidney injury (AKI) group than in the normal glomerular filtration rate (GFR) group. In the normal GFR group, the tacrolimus levels were identified as a risk factor for CKD, with a level of ≤4.5 ng/mL suggested as optimal for minimizing the risk of CKD. Furthermore, the IPV of tacrolimus levels and doses emerged as a significant risk factor for CKD development in both groups (P<0.05), with tenofovir disoproxil fumarate also being a risk factor in HBV-infected patients. The IPV of tacrolimus levels was also a significant factor in ESRD development (P<0.05). Conclusions: This study elucidated the optimal tacrolimus through level and highlighted the impact of IPV on the CKD and ESRD development post-LT.

The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome.

Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4+ regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.

Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicentre Cohort Study.

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.