Hepatology最新文献

{"title":"Distinct immune microenvironment of venous tumor thrombus in hepatocellular carcinoma at single-cell resolution.","authors":"Kai-Qian Zhou, Yu-Cheng Zhong, Ming-Fang Song, Yun-Fan Sun, Wei Zhu, Jian-Wen Cheng, Yang Xu, Ze-Fan Zhang, Peng-Xiang Wang, Zheng Tang, Jian Zhou, Li-Ye Zhang, Jia Fan, Xin-Rong Yang","doi":"10.1097/HEP.0000000000001182","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001182","url":null,"abstract":"<p><strong>Background aims: </strong>Portal vein tumor thrombus (PVTT) worsens the prognosis of hepatocellular carcinoma by increasing intrahepatic dissemination and inducing portal vein hypertension. However, the immune characteristics of PVTT remain unclear. Therefore, this study aims to explore the immune microenvironment in PVTT.</p><p><strong>Approach results: </strong>Time-of-flight mass cytometry (CyTOF) revealed that macrophages and monocytes were the dominant immune cell type in PVTT, with a higher proportion than in primary tumor (PT) and blood (54.1% vs. 26.3% and 9.1%, p<0.05). The differentially enriched clustering of inhibitory and regulatory immune cells in PVTT indicated an immune-suppressive environment. According to the single-cell RNA sequencing (scRNA-seq), TAM-C5AR1 was characterized by leukocyte chemotaxis and was the most common subpopulation in PVTT (36.7%). Multiple immunofluorescence staining showed that the C5aR+ TAM/Mφ were enriched in PVTT compared to both PT and liver, and positively correlated with C5a (r=0.559, p<0.001). Notably, THP-1 (monocyte cell line) was recruited by CSQT2 (PVTT cell line) and exhibited up-regulation of CD163, CD206, and PD-L1 upon stimulation. C5aR antagonist could reverse this. C5aR+ TAMs could also inhibit Granzyme B in CD8+ T cells. High infiltration of C5aR+ TAMs in PVTT correlated with poor differentiation (p<0.009), and was a risk factor for overall survival (p=0.003) and for re-formation of PVTT after resection (p=0.007).</p><p><strong>Conclusions: </strong>TAMs, especially C5aR+ TAMs, were enriched in PVTT. C5aR+ TAMs contribute to the development of PVTT and poor prognosis by reshaping the immunosuppressive environment.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced hepatitis B virus-specific immunity by combined neutralizing antibody therapy and DNA vaccination in a murine model of chronic hepatitis B infection","authors":"Maxime Beretta, Benjamin Vesin, Yu Wei, Cyril Planchais, Pierre Rosenbaum, Malika Ait-Goughoulte, Nadège Pelletier, David Hardy, Hugo Mouquet, Maryline Bourgine","doi":"10.1097/hep.0000000000001179","DOIUrl":"https://doi.org/10.1097/hep.0000000000001179","url":null,"abstract":"Background &amp; Aims: Successful treatment of chronic HBV infection remains a great challenge due to the difficulty in inducing efficient immune responses. Here, we investigated the therapeutic potential of DNA vaccination combined with a potent HBV broadly neutralizing antibody (bNAb) targeting the small surface viral antigen. Approach &amp; Results: C57BL/6 mice were transduced with adeno-associated virus (AAV)-HBV and were treated twice a week with HBV bNAb for 5 weeks. A DNA-based vaccine encoding the HBV core, envelope, and polymerase proteins was administered once to mice 3 weeks after initiating of antibody therapy. The antiviral effects and antigen-specific immune responses were evaluated before and for 8 weeks after therapeutic vaccination. Vaccine administration with or without antibody treatment induced the development of functional HBV-specific CD8+ T cells and envelope-specific resident memory T cells in the liver. The combination of antibody treatment and DNA vaccination enhanced the recruitment of B and CD8+ T lymphocytes into the liver of HBV-carrier mice two weeks after vaccination. However, although still detectable 2 months after vaccination, HBV-specific CD8+ T cells showed an exhausted phenotype, suggesting that they are dysfunctional. In contrast, a more effective control of antigenemia was observed following combination therapy, which was associated with the presence of HBs-specific memory B cells. Conclusions: Although the combination therapy did not result in a functional cure, our findings indicate it produced additive effects on the development of HBV-specific T cells in the liver immediately following treatment, offering a better insight into the mechanisms underlying hepatic tolerance.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"9 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stard1 promotes cholestatic liver injury and disease progression by sensitizing to bile acid hepatotoxicity","authors":"Laura Conde de la Rosa, Laura Fábrega, Sandra Torres, Susana Nuñez, Vicent Ribas, Paula Segalés, Ricardo Espinosa-Escudero, Estel Solsona, María Jesús Monte, Alvaro Diaz-Gonzalez, José J. G. Marin, Carmen García-Ruiz, Jose C. Fernandez-Checa","doi":"10.1097/hep.0000000000001184","DOIUrl":"https://doi.org/10.1097/hep.0000000000001184","url":null,"abstract":"Background and Aims: Cholestatic liver diseases (CLD) are often accompanied by hepatocellular injury, fibrosis, and cirrhosis due to the intracellular accumulation of solutes that cannot be excreted into bile, including bile acids (BAs). These are synthesized in hepatocytes from cholesterol mainly via the classic pathway and in a lower proportion through the mitochondrial acidic pathway. The latter requires STARD1-dependent cholesterol transport to the mitochondrial inner membrane for metabolism, whose contribution to BA-induced hepatotoxicity and CLD is unknown. Approach and Results: Here we show that patients with primary biliary cholangitis exhibit increased expression of STARD1 compared to control subjects. Mice with hepatocyte-specific <jats:italic toggle=\"yes\">Stard1</jats:italic> deletion (<jats:italic toggle=\"yes\">Stard1</jats:italic> <jats:sup>Δhep</jats:sup>) were more resistant to experimental models of complete (bile duct ligation, BDL) and chemical obstructive cholestasis-induced liver injury, inflammation and fibrosis than <jats:italic toggle=\"yes\">Stard1</jats:italic> <jats:sup> f/f </jats:sup> mice. <jats:italic toggle=\"yes\">Stard1</jats:italic> <jats:sup>Δhep</jats:sup> mice exhibited reduced hepatic BAs and mitochondrial cholesterol accumulation but increased mitochondrial GSH (mGSH) levels following BDL compared to <jats:italic toggle=\"yes\">Stard1</jats:italic> <jats:sup> f/f </jats:sup> mice. Pharmacological mGSH depletion sensitized primary mouse hepatocytes to a mix of BAs mimicking the profile seen in <jats:italic toggle=\"yes\">Stard1</jats:italic> <jats:sup>f/f</jats:sup> mice after BDL leading to increased inflammatory response and cytotoxicity. Conclusions: These findings highlight a role for STARD1 in cholestatic liver injury and suggest that its targeting may be of relevance for CLD.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"83 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exchangeable Copper in the Danish Cohort of Patients with Wilson Disease","authors":"Camilla Lorenzen, Karen Dons, Frederik T. Kirk, Emilie M. Lynderup, Peter Ott, Thomas D. Sandahl","doi":"10.1097/hep.0000000000001178","DOIUrl":"https://doi.org/10.1097/hep.0000000000001178","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"31 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miRNAs in HCC, pathogenesis, and targets","authors":"Guisheng Song, Xiaofan Yu, Hongtao Shi, Bo Sun, Stuart Amateau","doi":"10.1097/hep.0000000000001177","DOIUrl":"https://doi.org/10.1097/hep.0000000000001177","url":null,"abstract":"Liver cancer is the third leading cause of cancer-related mortality worldwide. Hepatocellular carcinoma (HCC), the most common type of primary liver cancer is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally-occurring small non-coding RNAs play crucial roles in HCC by simultaneously modulating expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as non-invasive diagnostic tools. Restoring or inhibiting specific miRNAs have offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, immune microenvironment in HCC and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"1 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal multiphasic pre-operative image-based deep-learning predicts hepatocellular carcinoma outcomes after curative surgery","authors":"Rex Wan-Hin Hui, Keith Wan-Hang Chiu, I-Cheng Lee, Chenlu Wang, Ho-Ming Cheng, Jianliang Lu, Xianhua Mao, Sarah Yu, Lok-Ka Lam, Lung-Yi Mak, Tan-To Cheung, Nam-Hung Chia, Chin-Cheung Cheung, Wai-Kuen Kan, Tiffany Cho-Lam Wong, Albert Chi-Yan Chan, Yi-Hsiang Huang, Man-Fung Yuen, Philip Leung-Ho Yu, Wai-Kay Seto","doi":"10.1097/hep.0000000000001180","DOIUrl":"https://doi.org/10.1097/hep.0000000000001180","url":null,"abstract":"Background: Hepatocellular carcinoma (HCC) recurrence frequently occurs after curative surgery. Histological microvascular-invasion (MVI) predicts recurrence but cannot provide pre-operative prognostication, whereas clinical prediction scores have variable performances. Methods: Recurr-NET, a multimodal multiphasic residual-network random survival forest deep-learning model incorporating pre-operative CT and clinical parameters, was developed to predict HCC recurrence. Pre-operative triphasic CT scans were retrieved from patients with resected histology-confirmed HCC from four centers in Hong Kong (Internal-cohort). The internal-cohort was randomly divided in an 8:2 ratio into training and internal-validation. External-testing was performed in an independent cohort from Taiwan. Results: Among 1231 patients (Age 62.4, 83.1% male, 86.8% viral hepatitis, median follow-up 65.1 months), cumulative HCC recurrence at years 2 and 5 were 41.8% and 56.4% respectively. Recurr-NET achieved excellent accuracy in predicting recurrence from years 1-5 (Internal cohort AUROC 0.770-0.857; External AUROC 0.758-0.798), significantly out-performing MVI (Internal AUROC 0.518-0.590; External AUROC 0.557-0.615) and multiple clinical risk scores (ERASL-PRE, ERASL-POST, DFT, and Shim scores) (Internal AUROC 0.523-0.587, External AUROC: 0.524-0.620) respectively (all <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001). Recurr-NET was superior to MVI in stratifying recurrence risks at year 2 (Internal: 72.5% vs. 50.0% in MVI; External: 65.3% vs. 46.6% in MVI) and year 5 (Internal: 86.4% vs. 62.5% in MVI; External: 81.4% vs. 63.8% in MVI) (all <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001). Recurr-NET was also superior to MVI in stratifying liver-related and all-cause mortality (all <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001). The performance of Recurr-NET remained robust in subgroup analyses. Conclusion: Recurr-NET accurately predicted HCC recurrence, out-performing MVI and clinical prediction scores respectively, highlighting its potential in pre-operative prognostication.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"85 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived CCL2 drives tumor growth and immunosuppression in IDH1-mutant cholangiocarcinoma","authors":"Daniel J. Zabransky, Emma Kartalia, Jae W. Lee, James M. Leatherman, Soren Charmsaz, Sara E. Young, Yash Chhabra, Sebastià Franch-Expósito, Martin Kang, Saumya Maru, Noushin Rastkari, Michael Davis, William Brian Dalton, Kiyoko Oshima, Marina Baretti, Nilofer S. Azad, Elizabeth M. Jaffee, Mark Yarchoan","doi":"10.1097/hep.0000000000001185","DOIUrl":"https://doi.org/10.1097/hep.0000000000001185","url":null,"abstract":"Background and aims: Isocitrate dehydrogenase 1 (<jats:italic toggle=\"yes\">IDH1</jats:italic>)-mutant cholangiocarcinoma (CCA) is a highly lethal subtype of hepatobiliary cancer that is often resistant to immune checkpoint inhibitor therapies. We evaluated the effects of <jats:italic toggle=\"yes\">IDH1</jats:italic>-mutations in CCA cells on the tumor immune microenvironment and identify opportunities for therapeutic intervention. Approach and results: Analysis of 2,606 human CCA tumors using deconvolution of RNA-sequencing data identified decreased CD8 T cell and increased M2-like tumor-associated macrophage (TAM) infiltration in <jats:italic toggle=\"yes\">IDH1</jats:italic>-mutant compared to <jats:italic toggle=\"yes\">IDH1</jats:italic>-wild type tumors. To model the tumor immune microenvironment of <jats:italic toggle=\"yes\">IDH1-</jats:italic>mutant CCA <jats:italic toggle=\"yes\">in vivo</jats:italic>, we generated an isogenic cell line panel of mouse SB1 CCA cells containing a heterozygous IDH1 R132C (SB1<jats:sup>mIDH1</jats:sup>) or control (SB1<jats:sup>WT</jats:sup>) cells using CRISPR-mediated homology directed repair. SB1<jats:sup>mIDH1</jats:sup> cells recapitulated features of human <jats:italic toggle=\"yes\">IDH1</jats:italic>-mutant CCA including D-2-HG production and increased M2-like TAM infiltration. SB1<jats:sup>mIDH1</jats:sup> cells and tumors produced increased levels of CCL2, a chemokine involved in recruitment and polarization of M2-like TAMs compared to wild type controls. <jats:italic toggle=\"yes\">In vivo</jats:italic> neutralization of CCL2 led to decreased M2-like TAM infiltration, reduced tumor size, and improved overall survival in mice harboring SB1<jats:sup>mIDH1</jats:sup> tumors. Conclusions: <jats:italic toggle=\"yes\">IDH1-</jats:italic>mutant CCA is characterized by increased abundance of M2-like TAMs. Targeting CCL2 remodels the tumor immune microenvironment and improves outcomes in preclinical models of <jats:italic toggle=\"yes\">IDH1</jats:italic>-mutant CCA, highlighting the role for myeloid-targeted immunotherapies in the treatment of this cancer.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"18 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic real-world outcomes with obeticholic acid in primary biliary cholangitis (HEROES): A trial emulation study design.","authors":"M Alan Brookhart, Tracy J Mayne, Charles Coombs, Alexander Breskin, Erik Ness, Leona Bessonova, Yucheng Julia Chu, Jing Li, Michael W Fried, Bettina E Hansen, Kris V Kowdley, David Jones, George Mells, Palak J Trivedi, Shaun Hiu, Dorcas N Kareithi, James Wason, Rachel Smith, John D Seeger, Gideon M Hirschfield","doi":"10.1097/HEP.0000000000001174","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001174","url":null,"abstract":"<p><strong>Background and aims: </strong>Primary biliary cholangitis (PBC) is a rare, progressive liver disease. Obeticholic acid (OCA) received accelerated approval for treating patients with PBC in whom ursodeoxycholic acid (UDCA) failed, based on a surrogate endpoint of reduction in alkaline phosphatase. Analysis of the long-term safety extension with 2 external control groups demonstrated a significant increase in event-free survival in OCA-treated patients. This fully real-world evidence study assessed the effect of OCA treatment on the clinical outcomes.</p><p><strong>Approach and results: </strong>This trial emulation used data from the Komodo Healthcare Map™ claims database linked to US national laboratory, transplant, and death databases. Patients with compensated PBC and intolerance/inadequate response to UDCA who initiated OCA therapy were compared with patients who were OCA-eligible but not OCA-treated. The primary endpoint was time to first occurrence of death, liver transplant, or hospitalization for hepatic decompensation, analyzed using a propensity-score weighted Cox proportional hazards model. Baseline prognostic factors were balanced using standardized morbidity ratio weighting. For the primary analysis, 4174 patients contributed 11,246 control index dates; 403 patients contributed OCA indexes. Weighted groups were well balanced. Median (95% CI) follow-up in the OCA and non-OCA arms was 9.3 (8.4-10.6) months and 17.5 (16.2-18.6) months (weighted population; censored at discontinuation). Eight events occurred in the OCA arm, 32 in the weighted control (HR=0.37; 95% CI=0.14-0.75; p<0.001). Effects were consistent for each component of the composite endpoint.</p><p><strong>Conclusions: </strong>We identified a 63% reduced risk of hospitalization for hepatic decompensation, liver transplant, or death in OCA-treated versus non-OCA-treated individuals.</p><p><strong>Trial registration: </strong>HEROES; ClinicalTrials.gov NCT05292872.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human T cells engineered with an HLA-A2-restricted murine T-cell receptor targeting Glypican 3 effectively control human hepatocellular carcinoma in mice.","authors":"Enric Vercher, Ángela Covo-Vergara, Enrique Conde, Mercedes Hernández-Rueda, Edurne Elizalde, Uxua Mancheño, Javier Glez-Vaz, Ibon Tamayo-Uria, Maritza R García-García, Marta Ferrer-Roig, Javier Marañón-Lopez, David Repáraz, Marta Ruiz, Ascensión López-Díaz de Cerio, Susana Inogés, Mercedes Iñarrairaegui, Juan J Lasarte, Bruno Sangro, Pablo Sarobe, Sandra Hervas-Stubbs","doi":"10.1097/HEP.0000000000001175","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001175","url":null,"abstract":"<p><strong>Background aims: </strong>Glypican-3 (GPC3) is a promising target for T-cell therapy in hepatocellular carcinoma (HCC). While chimeric antigen receptor (CAR) T cells targeting GPC3 have demonstrated therapeutic efficacy, their effectiveness is limited by challenges such as low persistence and shedding of surface GPC3. Natural T-cell receptors (TCRs) may serve as an alternative, though identifying GPC3-specific TCRs within the endogenous repertoire is difficult.</p><p><strong>Approach results: </strong>We immunized HLA-A2 transgenic mice with an adenovirus expressing human GPC3, identifying a panel of TCRs that recognize the GPC3(522-530) epitope. We cloned three murine GPC3-TCRs (TCR-A, TCR-B, and TCR-C) and engineered primary human T cells (TCR-T). TCR-T cells effectively recognized GPC3+HLA-A2+ human HCC cells, with recognition diminished by GPC3 silencing and HLA-A2 blockade. TCR-B-T and TCR-C-T cells showed the highest reactivity, with TCR-B-T cells exhibiting superior effector functions, proliferative capacity, and therapeutic efficacy in xenograft HCC models. Notable, TCR-B-T cells outperformed second-generation 41BB GPC3-specific CAR-T cells, attributed to lower exhaustion, enhanced proliferation, greater effector function, and improved resilience. Furthermore, mixed dosing of CAR-T and TCR-B-T cells was significantly more effective than staggered dosing of the same cell type, suggesting potential synergistic effects.</p><p><strong>Conclusion: </strong>Transgenic TCRs join forces with CARs, expanding the arsenal of GPC3-targeting receptors for HCC T-cell therapy.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medical treatment of primary sclerosing cholangitis: What have we learned and where are we going?","authors":"Tom H. Karlsen, Kristin Kaasen Jørgensen, Annika Bergquist","doi":"10.1097/hep.0000000000001172","DOIUrl":"https://doi.org/10.1097/hep.0000000000001172","url":null,"abstract":"It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for an ideal phase II and phase III study design, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism towards hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate prescription of compounds to people with PSC based on low-quality evidence.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"128 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}