1
|
Lee SK, Kwon JH, Jang JW, Bae SH, Yoon SK, Jung ES, Choi JY. The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome. Transplantation 2025; 109:784-793. [PMID: 39375899 DOI: 10.1097/tp.0000000000005220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
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.
Collapse
Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
2
|
Bao BJ, Kwon YIC, Dunbar EG, Rollins Z, Patel J, Ambrosio M, Bruno DA, Patel V, Julliard WA, Kasirajan V, Hashmi ZA. National Trends and Outcomes of Combined Lung-Liver Transplantation: An Analysis of the UNOS Registry. Lung 2025; 203:57. [PMID: 40281222 PMCID: PMC12031901 DOI: 10.1007/s00408-025-00811-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE Combined lung-liver transplant (CLLT) is a complex yet life-saving procedure for patients with simultaneous end-stage lung and liver disease. Given the geographical allocation change to the lung allocation score (LAS) in 2017 and the recent SARS-CoV-2 outbreak in 2019, we aim to provide an updated analysis of the patient selection and outcomes of CLLTs. METHODS The UNOS registry was used to identify all patients who underwent CLLT between January 2014 and June 2023. To account for the changes made to LAS in 2017, baseline characteristics and outcomes were compared between era 1 (before 2017) and era 2 (after 2017). Risk factors for mortality were analyzed using the Cox regression hazard models. Recipient survival of up to 3 years was analyzed using the Kaplan-Meier method. RESULTS 117 CLLTs were performed (77.8% in era 2). Donor organs experienced significantly longer ischemic times (p = 0.039) and traveled longer distances (p = 0.025) in era 2. However, recipient (p = 0.79) and graft (p = 0.41) survival remained comparable at up to 3 years post-transplant between eras. CLLTs demonstrated similar long-term survival to isolated lung transplants (p = 0.73). Higher recipient LAS was associated with an increased mortality risk (HR 1.14, p = 0.034). Recipient diagnosis of idiopathic pulmonary fibrosis carried a 5.03-fold risk of mortality (p = 0.048) compared to those with cystic fibrosis. CONCLUSION In the post-2017 LAS change era, CLLTs are increasingly performed with comparable outcomes to isolated lung transplants. A careful, multidisciplinary approach to patient selection and management remains paramount to optimizing outcomes for this rare patient population.
Collapse
Affiliation(s)
- Brian J Bao
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Ye In Christopher Kwon
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Emily G Dunbar
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Zachary Rollins
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Jay Patel
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Matthew Ambrosio
- Department of Biostatistics, Virginia Commonwealth University School of Population Health, Richmond, VA, USA
| | - David A Bruno
- Division of Abdominal Transplant Surgery, Department of Surgery, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Vipul Patel
- Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Walker A Julliard
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Vigneshwar Kasirajan
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Zubair A Hashmi
- Division of Cardiothoracic Surgery, Department of Surgery, Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| |
Collapse
|
3
|
Yang X, Ming Y, Zhou Z, Zhou X, Rao C. Identification of key immune genes of drug-induced liver injury induced by tolvaptan based on bioinformatics. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04084-0. [PMID: 40178603 DOI: 10.1007/s00210-025-04084-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 03/20/2025] [Indexed: 04/05/2025]
Abstract
Drug-induced liver injury (DILI) poses critical challenges in preclinical drug development and is a primary reason for candidate drug attrition. The incidence of DILI has risen in recent years. While immune-related genes (IRGs) are crucial in immune infiltration, their expression and regulatory mechanisms in tolvaptan-induced DILI remain largely uncharacterized. RNA sequencing data related to DILI and associated clinical data were sourced from the Gene Expression Omnibus (GEO), and IRGs were obtained from the ImmPort database. Differentially expressed genes (DEGs) from DILI and IRGs were intersected to identify differentially expressed immune-related genes (DEIRGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to elucidate the biological functions of DEIRGs. In addition, a protein-protein interaction (PPI) network of DEIRGs was constructed. Immunocytes and immune regulation analyses were conducted using the CIBERSORT tool. Receiver operating characteristic (ROC) curves were constructed to assess the diagnostic accuracy of individual DEIRGs. Networks of transcription factor and microRNA co-regulation were constructed using the NetworkAnalyst database. The expression of DEIRGs in DILI samples was quantified with RT-qPCR. From GSE99878, 204 DEGs were identified, with 23 matching IRGs exhibiting significant expression differences in 17 DEIRGs. The ROC curve analysis suggested satisfactory diagnostic values for six DEIRGs. The potential gene regulatory network comprised 214 microRNAs, 257 transcription factors, and 23 DEIRGs. Finally, RT-qPCR confirmed the expression levels of nine DEIRGs, aligning with public database results. The study revealed numerous immune-related biomarkers, verifying expression in five pivotal genes (ICAM1, CXCL10, IGF1, CX3CL1, and EGFR) and highlighting four genes with notable diagnostic potential (TNFAIP3, BDNF, NR1D2, and PPARA). Additionally, it explored the roles of key biomarkers in inflammatory responses, relevant signaling pathways, and interaction networks, offering new insights into DILI diagnosis, mechanistic understanding, and treatment strategies.
Collapse
Affiliation(s)
- Xiyun Yang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu Sichuan, 611137, China
| | - Yuxuan Ming
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu Sichuan, 611137, China
| | - Zhihui Zhou
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu Sichuan, 611137, China
| | - Xinyi Zhou
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu Sichuan, 611137, China
| | - Chaolong Rao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu Sichuan, 611137, China.
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu Sichuan, 611137, China.
- R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu City, 611137, Sichuan, China.
| |
Collapse
|
4
|
Taner T, Biggins SW, Cummins N, Daly RC, Dietz AB, Emamaullee J, Gandhi MJ, Heimbach JK, Patel JK, Pereira NL, Rosenbaum A, Sanchez-Fueyo A, Shingina A, Stegall MD, Villavicencio Theoduloz MA, Wald JW, Kushwaha SS. Summary of a Consensus Conference on the Management of Highly Sensitized Multiorgan Transplant Candidates. Mayo Clin Proc 2025; 100:700-711. [PMID: 40057871 DOI: 10.1016/j.mayocp.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/26/2024] [Accepted: 01/20/2025] [Indexed: 04/05/2025]
Abstract
The number of highly sensitized patients in need of a multiorgan transplant is increasing. Criteria informing their transplant candidacy, approaches to management on the waitlist, and protocols related to alloantibody monitoring vary widely. We convened a consensus conference to discuss these different practices in the United States and the United Kingdom and to review the contemporary outcomes of these challenging cases. A detailed analysis of the data regarding the liver allografts' immunoprotective effect on simultaneously transplanted other organs was also completed, and the prospect of the use of liver allografts primarily to facilitate transplantation of highly sensitized patients in need of other organs was discussed. The ethical and allocation-related issues about such prospect were debated with a goal to standardize the approach and provide an evidence-based pathway for pre-, peri-, and post-transplantation management for the highly sensitized multiorgan transplantation candidate.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Joyce W Wald
- University of Pennsylvania, Philadelphia, PA, USA
| | | |
Collapse
|
5
|
Liu QL, Zhou H, Wang Z, Chen Y. Exploring the role of gut microbiota in colorectal liver metastasis through the gut-liver axis. Front Cell Dev Biol 2025; 13:1563184. [PMID: 40181829 PMCID: PMC11965903 DOI: 10.3389/fcell.2025.1563184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Colorectal liver metastasis (CRLM) represents a major therapeutic challenge in colorectal cancer (CRC), with complex interactions between the gut microbiota and the liver tumor microenvironment (TME) playing a crucial role in disease progression via the gut-liver axis. The gut barrier serves as a gatekeeper, regulating microbial translocation, which influences liver colonization and metastasis. Through the gut-liver axis, the microbiota actively shapes the TME, where specific microbial species and their metabolites exert dual roles in immune modulation. The immunologically "cold" nature of the liver, combined with the influence of the gut microbiota on liver immunity, complicates effective immunotherapy. However, microbiota-targeted interventions present promising strategies to enhance immunotherapy outcomes by modulating the gut-liver axis. Overall, this review highlights the emerging evidence on the role of the gut microbiota in CRLM and provides insights into the molecular mechanisms driving the dynamic interactions within the gut-liver axis.
Collapse
Affiliation(s)
- Qiu-Luo Liu
- Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Institute of Digestive Surgery, Institute of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huijie Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Health Management Center, General Practice Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ziqiang Wang
- Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Chen
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
6
|
Shrestha S, Jeon JH, Hong CW. Neutrophils in MASLD and MASH. BMB Rep 2025; 58:116-123. [PMID: 39757200 PMCID: PMC11955729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/23/2024] [Accepted: 06/11/2024] [Indexed: 01/07/2025] Open
Abstract
Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic Dysfunction Associated Steatohepatitis (MASH), represent significant health concerns associated with the metabolic syndrome. These conditions are characterized by excessive hepatic fat accumulation, inflammation, and potential progression to cirrhosis and hepatocellular carcinoma. Neutrophils are innate immune cells that play a pivotal role in the development of MASLD and MASH. They can infiltrate the hepatic microenvironment in response to inflammatory cytokines and damage associated molecular patterns (DAMPs) derived from the liver and exacerbate tissue damage by releasing of reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps (NETs). Moreover, neutrophils can disrupt the metabolism of hepatocytes through key factors such as neutrophil elastase (NE) and human neutrophil peptides-1 (HNP-1), leading to inflammation and fibrosis, while myeloperoxidase (MPO) and lipocalin (LCN2) are involved in inflammatory and fibrotic processes. In contrast, neutrophils contribute to liver protection and repair through mechanisms involving microRNA-223 and matrix metalloproteinase 9 (MMP9). This dual role of neutrophils highlights their significance in the pathogenesis of MASLD and MASH. This review summarizes current understanding from recent studies on the involvement of neutrophils in MASLD and MASH. Understanding complex roles of neutrophils within the liver's unique microenvironment offers insights into novel therapeutic strategies, emphasizing the need for further research to explore neutrophil-targeted interventions for managing MASLD and MASH. [BMB Reports 2025; 58(3): 116-123].
Collapse
Affiliation(s)
- Sanjeeb Shrestha
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Jae-Han Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, Korea
| | - Chang-Won Hong
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
- Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Korea
| |
Collapse
|
7
|
Fumagalli V, Iannacone M. Unlocking CD8 + T cell potential in chronic hepatitis B virus infection. Nat Rev Gastroenterol Hepatol 2025; 22:92-93. [PMID: 39551880 DOI: 10.1038/s41575-024-01015-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Affiliation(s)
- Valeria Fumagalli
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| |
Collapse
|
8
|
Henriques-Pons A, Vacani-Martins N, dos Santos CDLP, Meuser-Batista M. The liver's dilemma: sensing real danger in a sea of PAMPs: the (arterial) sinusoidal segment theory. Front Immunol 2025; 15:1503063. [PMID: 39931578 PMCID: PMC11808282 DOI: 10.3389/fimmu.2024.1503063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/30/2024] [Indexed: 02/13/2025] Open
Abstract
The liver is susceptible to viruses and bacterial infections, tumors, and sterile tissue damage, but immunological danger recognition in the liver is highly unconventional. When analyzing innate and adaptive immunity in the organ, the valid concepts that guide danger recognition and immune response in the periphery should be put aside. In the liver, the vascular anatomy is a game changer, as about 80% of the blood that percolates the organ arrives from the hepatic portal vein, draining blood rich in molecules from the intestinal flora. This 24/7 exposure to high amounts of pathogen-associated molecular pattern (PAMPs) molecules results in hepatic immunological tolerance. In the liver, dendritic, Kupffer (KC), liver sinusoidal endothelial cells (LSECs), and even hepatocytes express PD-L1, a T lymphocyte downregulatory molecule. Most cells express Fas-L, IL-10, TGF-β, low levels of co-stimulatory molecules, lack of or have low levels of MHC-I and/or MHC-II expression. Moreover, other negative regulators such as CTLA-4, IDO-1, and prostaglandin E2 (PGE2) are regularly expressed. Then, how can real danger be discerned and recognized in this sea of PAMPs? This is an open question. Here, we hypothesize that conventional immunological danger recognition can occur in the liver but in specific and minor arterial sinusoidal segments,. Then, in the portal triad, where the hepatic artery ramificates into the stroma and carries arterial blood with no gut-derived PAMPs, there is no evolutive or environmental pressure for immunosuppressive pathways, and conventional immunological danger recognition could occur. Therefore, in arterial sinusoidal segments with no sea of PAMPs, the liver could recognize real danger and support innate and adaptive immunity.
Collapse
Affiliation(s)
- Andrea Henriques-Pons
- Laboratorio de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Natália Vacani-Martins
- Laboratorio de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Marcelo Meuser-Batista
- Laboratório de Educação Profissional em Técnicas Laboratoriais em Saúde, Escola Politecnica de Saúde Joaquim Venâncio, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| |
Collapse
|
9
|
Dhayanithy G, Radhakrishnan S, Ann Martin C, Caroline Martin J, Hakeem AR, Jothimani D, Kalkura SN, Rela M. Understanding immunological insights of liver transplantation: a practice for attaining operational tolerance. Clin Exp Immunol 2025; 219:uxae125. [PMID: 39973343 PMCID: PMC11878573 DOI: 10.1093/cei/uxae125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 11/15/2024] [Accepted: 02/19/2025] [Indexed: 02/21/2025] Open
Abstract
Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.
Collapse
Affiliation(s)
| | | | | | - Josette Caroline Martin
- Department of Pathology, Sri Venkateshwara Medical College Hospital and Research Institute, Pondicherry, India
| | | | - Dinesh Jothimani
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
| | - Subbaraya Narayana Kalkura
- Crystal Growth Centre, Anna University, Guindy, Chennai, India
- National Foundation for Liver Research, Chromepet, Chennai, India
| | - Mohamed Rela
- National Foundation for Liver Research, Chromepet, Chennai, India
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
| |
Collapse
|
10
|
Han JW, Park SH. Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:257-272. [PMID: 39696994 PMCID: PMC11732766 DOI: 10.4285/ctr.24.0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.
Collapse
Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
| |
Collapse
|
11
|
De Martin E, Fulgenzi CAM, Celsa C, Laurent-Bellue A, Torkpour A, Lombardi P, D'Alessio A, Pinato DJ. Immune checkpoint inhibitors and the liver: balancing therapeutic benefit and adverse events. Gut 2024:gutjnl-2024-332125. [PMID: 39658265 DOI: 10.1136/gutjnl-2024-332125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/19/2024] [Indexed: 12/12/2024]
Abstract
Immune checkpoint inhibitors (ICI) have led to breakthrough improvements in the management of malignancy including hepatocellular (HCC) and biliary tract cancer, improving decades-old standards of care and increasing patient survival. In both liver tumour types, which commonly arise in the context of liver inflammation and underlying functional impairment, the lack of validated predictors of response underscores the need to balance predicted gains in survival with risk of treatment-related hepatoxicity and decompensation of underlying chronic liver disease.In addition, the liver is implicated in the toxicity associated with ICI therapy for non-liver cancers, which exhibits a high degree of variability in presentation and severity. An accurate assessment is mandatory for the diagnosis and management of ICI-induced liver injury.In this Recent Advances article, we provide an overview of the mechanisms of efficacy and toxicity of anticancer immunotherapy in liver tumours and liver toxicity in extrahepatic malignancies.We compare and contrast characteristics, management strategies and outcomes from immune-related liver injury in patients with chronic hepatitis/cirrhosis or with an underlying healthy liver and discuss the latest findings on how toxicity and decompensation may impact the outlook of patients with liver tumours and extrahepatic malignancies offering insights into the future directions of clinical research and practice in the field.
Collapse
Affiliation(s)
- Eleonora De Martin
- Centre Hepatobiliaire, Paul Brousse Hospital, Villejuif, France
- Paris-Saclay University, Faculty of Medicine, Le Kremlin-Bicetre, France
| | | | - Ciro Celsa
- Surgery & Cancer, Imperial College London, London, UK
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, Gastroenterology and Hepatology Unit, Palermo, Italy
| | - Astrid Laurent-Bellue
- Hôpital Kremlin Bicêtre, Anatomie & Cytologie Pathologiques, Le Kremlin Bicetre, France
| | - Aria Torkpour
- Surgery & Cancer, Imperial College London, London, UK
| | - Pasquale Lombardi
- Surgery & Cancer, Imperial College London, London, UK
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Antonio D'Alessio
- Surgery & Cancer, Imperial College London, London, UK
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - David J Pinato
- Surgery & Cancer, Imperial College London, London, UK
- Imperial College London, University of Eastern Piedmont Amedeo Avogadro, Department of Translational Medicine, Novara, Italy
| |
Collapse
|
12
|
Bertoletti A. The immune response in chronic HBV infection. J Viral Hepat 2024; 31 Suppl 2:43-55. [PMID: 38845402 DOI: 10.1111/jvh.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 12/06/2024]
Abstract
Hepatitis B virus (HBV) is an ancient virus that has evolved unique strategies to persist as a chronic infection in humans. Here, I summarize the innate and adaptive features of the HBV-host interaction, and I discuss how different profiles of antiviral immunity cannot be predicted only on the basis of virological and clinical parameters.
Collapse
Affiliation(s)
- Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
| |
Collapse
|
13
|
Hildebrandt F, Iturritza MU, Zwicker C, Vanneste B, Van Hul N, Semle E, Quin J, Pascini T, Saarenpää S, He M, Andersson ER, Scott CL, Vega-Rodriguez J, Lundeberg J, Ankarklev J. Host-pathogen interactions in the Plasmodium-infected mouse liver at spatial and single-cell resolution. Nat Commun 2024; 15:7105. [PMID: 39160174 PMCID: PMC11333755 DOI: 10.1038/s41467-024-51418-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 08/06/2024] [Indexed: 08/21/2024] Open
Abstract
Upon infecting its vertebrate host, the malaria parasite initially invades the liver where it undergoes massive replication, whilst remaining clinically silent. The coordination of host responses across the complex liver tissue during malaria infection remains unexplored. Here, we perform spatial transcriptomics in combination with single-nuclei RNA sequencing over multiple time points to delineate host-pathogen interactions across Plasmodium berghei-infected liver tissues. Our data reveals significant changes in spatial gene expression in the malaria-infected tissues. These include changes related to lipid metabolism in the proximity to sites of Plasmodium infection, distinct inflammation programs between lobular zones, and regions with enrichment of different inflammatory cells, which we term 'inflammatory hotspots'. We also observe significant upregulation of genes involved in inflammation in the control liver tissues of mice injected with mosquito salivary gland components. However, this response is considerably delayed compared to that observed in P. berghei-infected mice. Our study establishes a benchmark for investigating transcriptome changes during host-parasite interactions in tissues, it provides informative insights regarding in vivo study design linked to infection and offers a useful tool for the discovery and validation of de novo intervention strategies aimed at malaria liver stage infection.
Collapse
Affiliation(s)
- Franziska Hildebrandt
- Molecular Biosciences, the Wenner Gren Institute, Stockholm University, Svante Arrhenius Väg 20C, SE-106 91, Stockholm, Sweden.
| | - Miren Urrutia Iturritza
- Molecular Biosciences, the Wenner Gren Institute, Stockholm University, Svante Arrhenius Väg 20C, SE-106 91, Stockholm, Sweden
| | - Christian Zwicker
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent, 9052, Belgium
| | - Bavo Vanneste
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent, 9052, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent, 9052, Belgium
| | - Noémi Van Hul
- Department of Cell and Molecular Biology, Karolinska Institutet Stockholm, SE-171 77, Solna, Sweden
| | - Elisa Semle
- Molecular Biosciences, the Wenner Gren Institute, Stockholm University, Svante Arrhenius Väg 20C, SE-106 91, Stockholm, Sweden
| | - Jaclyn Quin
- Molecular Biosciences, the Wenner Gren Institute, Stockholm University, Svante Arrhenius Väg 20C, SE-106 91, Stockholm, Sweden
| | - Tales Pascini
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rm 2E20A, Rockville, MD, 20852, USA
| | - Sami Saarenpää
- SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology, Tomtebodavägen 23a, SE-171 65, Solna, Sweden
| | - Mengxiao He
- SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology, Tomtebodavägen 23a, SE-171 65, Solna, Sweden
| | - Emma R Andersson
- Department of Cell and Molecular Biology, Karolinska Institutet Stockholm, SE-171 77, Solna, Sweden
| | - Charlotte L Scott
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent, 9052, Belgium
| | - Joel Vega-Rodriguez
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rm 2E20A, Rockville, MD, 20852, USA
| | - Joakim Lundeberg
- SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology, Tomtebodavägen 23a, SE-171 65, Solna, Sweden
| | - Johan Ankarklev
- Molecular Biosciences, the Wenner Gren Institute, Stockholm University, Svante Arrhenius Väg 20C, SE-106 91, Stockholm, Sweden.
| |
Collapse
|
14
|
Yue B, Gao Y, Hu Y, Zhan M, Wu Y, Lu L. Harnessing CD8 + T cell dynamics in hepatitis B virus-associated liver diseases: Insights, therapies and future directions. Clin Transl Med 2024; 14:e1731. [PMID: 38935536 PMCID: PMC11210506 DOI: 10.1002/ctm2.1731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/29/2024] Open
Abstract
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
Collapse
Affiliation(s)
- Bing Yue
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yuxia Gao
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yi Hu
- Microbiology and Immunology DepartmentSchool of MedicineFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| |
Collapse
|
15
|
Fu Z, Liu J, Zhang C, Hu H, Li S, Zhang Y, You R. Hepatitis-related adverse events associated with immune checkpoint inhibitors in cancer patients: an observational, retrospective, pharmacovigilance study using the FAERS database. Front Pharmacol 2024; 15:1383212. [PMID: 38948476 PMCID: PMC11211592 DOI: 10.3389/fphar.2024.1383212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/28/2024] [Indexed: 07/02/2024] Open
Abstract
Background: Immune checkpoint inhibitors (ICIs), including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, have become a standard treatment for multiple cancer types. However, ICIs can induce immune-related adverse events, with hepatitis-related adverse events (HRAEs) being of particular concern. Our objective is to identify and characterize HRAEs that exhibit a significant association with ICIs using real-world data. Methods: In this observational and retrospective pharmacovigilance study, we extracted real-world adverse events reports from the FDA Adverse Event Reporting System database spanning from the first quarter of 2004 to the first quarter of 2023. We conducted both Frequentist and Bayesian methodologies in the framework of disproportionality analysis, which included the reporting odds ratios (ROR) and information components (IC) to explore the intricate relationship between ICIs and HRAEs. Results: Through disproportionality analysis, we identified three categories of HRAEs as being significantly related with ICIs, including autoimmune hepatitis (634 cases, ROR 19.34 [95% CI 17.80-21.02]; IC025 2.43), immune-mediated hepatitis (546 cases, ROR 217.24 [189.95-248.45]; IC025 4.75), and hepatitis fulminant (80 cases, ROR 4.56 [3.65-5.70]; IC025 0.49). The median age of patients who report ICI-related HRAEs was 63 years (interquartile range [IQR] 53.8-72), with a fatal outcome observed in 24.9% (313/1,260) of these reports. Cases pertaining to skin cancer, lung cancer, and kidney cancer constituted the majority of these occurrences. Patients treated with anti-PD-1 or anti-PD-L1 antibodies exhibited a higher frequency of immune-mediated hepatitis in comparison to those undergoing anti-CTLA-4 monotherapy, with a ROR of 3.59 (95% CI 1.78-6.18). Moreover, the dual ICI therapy demonstrated higher reporting rates of ICI-related HRAEs compared to ICI monotherapy. Conclusion: Our findings confirm that ICI treatment carries a significant risk of severe HRAEs, in particular autoimmune hepatitis, immune-mediated hepatitis, and hepatitis fulminant. Healthcare providers should exercise heightened vigilance regarding these risks when managing patients receiving ICIs.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Ruxu You
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
16
|
Papadopoulos G, Giannousi E, Avdi AP, Velliou RI, Nikolakopoulou P, Chatzigeorgiou A. Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma. Front Cell Dev Biol 2024; 12:1343806. [PMID: 38774646 PMCID: PMC11106433 DOI: 10.3389/fcell.2024.1343806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is the progressed version of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by inflammation and fibrosis, but also a pathophysiological "hub" that favors the emergence of liver malignancies. Current research efforts aim to identify risk factors, discover disease biomarkers, and aid patient stratification in the context of MASH-induced hepatocellular carcinoma (HCC), the most prevalent cancer among MASLD patients. To investigate the tumorigenic transition in MASH-induced HCC, researchers predominantly exploit preclinical animal-based MASH models and studies based on archived human biopsies and clinical trials. Recapitulating the immune response during tumor development and progression is vital to obtain mechanistic insights into MASH-induced HCC. Notably, the advanced complexity behind MASLD and MASH pathogenesis shifted the research focus towards innate immunity, a fundamental element of the hepatic immune niche that is usually altered robustly in the course of liver disease. During the last few years, however, there has been an increasing interest for deciphering the role of adaptive immunity in MASH-induced HCC, particularly regarding the functions of the various T cell populations. To effectively understand the specific role of T cells in MASH-induced HCC development, scientists should urgently fill the current knowledge gaps in this field. Pinpointing the metabolic signature, sketching the immune landscape, and characterizing the cellular interactions and dynamics of the specific T cells within the MASH-HCC liver are essential to unravel the mechanisms that adaptive immunity exploits to enable the emergence and progression of this cancer. To this end, our review aims to summarize the current state of research regarding the T cell functions linked to MASH-induced HCC.
Collapse
Affiliation(s)
- Grigorios Papadopoulos
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eirini Giannousi
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini P. Avdi
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Rallia-Iliana Velliou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Polyxeni Nikolakopoulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
- Center for the Advancement of Integrated Medical and Engineering Sciences (AIMES), Karolinska Institute and KTH Royal Institute of Technology, Stockholm, Sweden
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
17
|
Zhou AW, Jin J, Liu Y. Cellular strategies to induce immune tolerance after liver transplantation: Clinical perspectives. World J Gastroenterol 2024; 30:1791-1800. [PMID: 38659486 PMCID: PMC11036497 DOI: 10.3748/wjg.v30.i13.1791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/03/2024] [Accepted: 03/14/2024] [Indexed: 04/03/2024] Open
Abstract
Liver transplantation (LT) has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management. However, long-term side-effects of immunosuppressants, like infection, metabolic disorders and malignant tumor are gaining more attention. Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants, but the liver function and intrahepatic histology maintain normal. The approaches to achieve immune tolerance after transplantation include spontaneous, operational and induced tolerance. The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up. No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation. With the understanding to the underlying mechanisms of immune tolerance, many strategies have been developed to induce tolerance in LT recipients. Cellular strategy is one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells. The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials, while obstacles still exist before translating into clinical practice. Here, we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.
Collapse
Affiliation(s)
- Ai-Wei Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jing Jin
- Department of Nursing, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yuan Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Department of Liver Transplantation, Shanghai Immune Therapy Institute, Shanghai 200127, China
| |
Collapse
|
18
|
Gudd CLC, Mitchell E, Atkinson SR, Mawhin MA, Turajlic S, Larkin J, Thursz MR, Goldin RD, Powell N, Antoniades CG, Woollard KJ, Possamai LA, Triantafyllou E. Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis. J Immunother Cancer 2024; 12:e008078. [PMID: 38580334 PMCID: PMC11002390 DOI: 10.1136/jitc-2023-008078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. METHODS C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) ("CPI") or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivo investigations of CPI-hepatitis were carried out in Rag2-/- and Ccr2rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment. RESULTS Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+ T cells and CCR2+ monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+ T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2+ monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis. CONCLUSION This newly established mouse model provides a platform for in vivo mechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2+ monocyte interaction with tissue-destructive CD8+ T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target.
Collapse
Affiliation(s)
- Cathrin L C Gudd
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Eoin Mitchell
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Stephen R Atkinson
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Marie-Anne Mawhin
- Centre for Inflammatory Disease, Imperial College London, London, UK
| | - Samra Turajlic
- Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK
- Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK
- Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
| | - James Larkin
- Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK
- Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
| | - Mark R Thursz
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Robert D Goldin
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Nick Powell
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | | | - Kevin J Woollard
- Centre for Inflammatory Disease, Imperial College London, London, UK
| | - Lucia A Possamai
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | | |
Collapse
|
19
|
Wang K, Wu J, Yang Z, Zheng B, Shen S, Wang RR, Zhang Y, Wang HY, Chen L, Qiu X. Hyperactivation of β-catenin signal in hepatocellular carcinoma recruits myeloid-derived suppressor cells through PF4-CXCR3 axis. Cancer Lett 2024; 586:216690. [PMID: 38307410 DOI: 10.1016/j.canlet.2024.216690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/17/2024] [Accepted: 01/26/2024] [Indexed: 02/04/2024]
Abstract
The high mutation rate of CTNNB1 (37 %) and Wnt-β-catenin signal-associated genes (54 %) has been notified in hepatocellular carcinoma (HCC). The activation of Wnt-β-catenin signal pathway was reported to be associated with an immune "desert" phenotype, but the underlying mechanism remains unclear. Here we mainly employed orthotopic HCC models to explore on it. Mass cytometry depicted the immune contexture of orthotopic HCC syngeneic grafts, unveiling that the exogenous expression of β-catenin significantly increased the percentage of myeloid-derived suppressor cells (MDSCs) and decreased the percentage of CD8+ T-cells. Flow cytometry and immunohistochemistry further confirmed the findings. The protein microarray analysis, Western blot and PCR identified PF4 as its downstream regulating cytokine. Intratumorally injection of cytokine PF4 enhanced the accumulation of MDSCs. Knockout of PF4 abolished the effect of β-catenin on recruiting MDSCs. Chromatin immunoprecipitation and luciferase reporter assay demonstrated that β-catenin increases the mRNA level of PF4 via binding to PF4's promoter region. In vitro chemotaxis assay and in vivo administration of specific inhibitors identified CXCR3 on MDSCs as receptor for recruiting PF4. Lastly, the significant correlations across β-catenin, PF4 and MDSCs and CD8+ T-cells infiltration were verified in HCC clinical samples. Our results unveiled HCC tumor cell intrinsic hyperactivation of β-catenin can recruit MDSC through PF4-CXCR3, which contributes to the formation of immune "desert" phenotype. Our study provided new insights into the development of immunotherapeutic strategy of HCC with CTNNB1 mutation. SIGNIFICANCE: This study identifies PF4-CXCR3-MDSCs as a downstream mechanism underlying CTNNB1 mutation associated immune "desert" phenotype.
Collapse
Affiliation(s)
- Kaiting Wang
- School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China
| | - Jianmin Wu
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China
| | - Zhao Yang
- Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China
| | - Bo Zheng
- The International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, 200441, China
| | - Siyun Shen
- The International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, 200441, China
| | - Rui-Ru Wang
- Berry Oncology Corporation, Digital Fujian Park, Fuzhou, China
| | - Yani Zhang
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China
| | - Hong-Yang Wang
- The International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, 200441, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China.
| | - Lei Chen
- The International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, China; Department of Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Xinyao Qiu
- Department of Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
20
|
Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
Collapse
Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| |
Collapse
|
21
|
López CAM, Freiberger RN, Sviercz FA, Quarleri J, Delpino MV. HIV-Infected Hepatic Stellate Cells or HCV-Infected Hepatocytes Are Unable to Promote Latency Reversal among HIV-Infected Mononuclear Cells. Pathogens 2024; 13:134. [PMID: 38392872 PMCID: PMC10893349 DOI: 10.3390/pathogens13020134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/23/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Due to a common mode of transmission through infected human blood, hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is relatively prevalent. In alignment with this, HCV co-infection is associated with an increased size of the HIV reservoir in highly active antiretroviral therapy (HAART)-treated individuals. Hence, it is crucial to comprehend the physiological mechanisms governing the latency and reactivation of HIV in reservoirs. Consequently, our study delves into the interplay between HCV/HIV co-infection in liver cells and its impact on the modulation of HIV latency. We utilized the latently infected monocytic cell line (U1) and the latently infected T-cell line (J-Lat) and found that mediators produced by the infection of hepatic stellate cells and hepatocytes with HIV and HCV, respectively, were incapable of inducing latency reversal under the studied conditions. This may favor the maintenance of the HIV reservoir size among latently infected mononuclear cells in the liver. Further investigations are essential to elucidate the role of the interaction between liver cells in regulating HIV latency and/or reactivation, providing a physiologically relevant model for comprehending reservoir microenvironments in vivo.
Collapse
Affiliation(s)
| | | | | | - Jorge Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1121, Argentina; (C.A.M.L.); (R.N.F.)
| | - María Victoria Delpino
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1121, Argentina; (C.A.M.L.); (R.N.F.)
| |
Collapse
|
22
|
Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med 2024; 95:101231. [PMID: 38056058 DOI: 10.1016/j.mam.2023.101231] [Citation(s) in RCA: 53] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/13/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023]
Abstract
Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.
Collapse
Affiliation(s)
- Maurizio Parola
- Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine - Royal Free Hospital, London, NW32PF, United Kingdom.
| |
Collapse
|
23
|
Benner SE, Zhu X, Hussain S, Florman S, Eby Y, Fernandez RE, Ostrander D, Rana M, Ottmann S, Hand J, Price JC, Pereira MR, Wojciechowski D, Simkins J, Stosor V, Mehta SA, Aslam S, Malinis M, Haidar G, Massie A, Smith ML, Odim J, Morsheimer M, Quinn TC, Laird GM, Siliciano R, Balagopal A, Segev DL, Durand CM, Redd AD, Tobian AAR. HIV-Positive Liver Transplant Does not Alter the Latent Viral Reservoir in Recipients With Antiretroviral Therapy-Suppressed HIV. J Infect Dis 2023; 228:1274-1279. [PMID: 37379584 PMCID: PMC10629701 DOI: 10.1093/infdis/jiad241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/02/2023] [Accepted: 06/22/2023] [Indexed: 06/30/2023] Open
Abstract
The latent viral reservoir (LVR) remains a major barrier to HIV-1 curative strategies. It is unknown whether receiving a liver transplant from a donor with HIV might lead to an increase in the LVR because the liver is a large lymphoid organ. We found no differences in intact provirus, defective provirus, or the ratio of intact to defective provirus between recipients with ART-suppressed HIV who received a liver from a donor with (n = 19) or without HIV (n = 10). All measures remained stable from baseline by 1 year posttransplant. These data demonstrate that the LVR is stable after liver transplantation in people with HIV. Clinical Trials Registration. NCT02602262 and NCT03734393.
Collapse
Affiliation(s)
- Sarah E Benner
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Xianming Zhu
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Sarah Hussain
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Sander Florman
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yolanda Eby
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Reinaldo E Fernandez
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Darin Ostrander
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Meenakshi Rana
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Shane Ottmann
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Health, New Orleans, Louisiana, USA
| | - Jennifer C Price
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Marcus R Pereira
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - David Wojciechowski
- Division of Nephrology, University of Texas Southwestern, Dallas, Texas, USA
| | - Jacques Simkins
- Department of Medicine/Division of Infectious Diseases, University of Miami School of Medicine, Miami, Florida, USA
| | - Valentina Stosor
- Departments of Medicine and Surgery, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Sapna A Mehta
- Department of Medicine, New York University Grossman School of Medicine, New York University Langone Health, New York, New York, USA
| | - Saima Aslam
- Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, California, USA
| | - Maricar Malinis
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Ghady Haidar
- Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Allan Massie
- Department of Surgery, New York University Grossman School of Medicine, New York University Langone Health, New York, New York, USA
| | - Melissa L Smith
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, USA
| | - Jonah Odim
- Division of Extramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Megan Morsheimer
- Division of Extramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Thomas C Quinn
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Robert Siliciano
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Ashwin Balagopal
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Dorry L Segev
- Department of Surgery, New York University Grossman School of Medicine, New York University Langone Health, New York, New York, USA
| | - Christine M Durand
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Andrew D Redd
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Aaron A R Tobian
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
24
|
Gebru YA, Pang MG. Modulatory effects of bisphenol A on the hepatic immune response. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 336:122430. [PMID: 37611793 DOI: 10.1016/j.envpol.2023.122430] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/16/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
The liver is a primary line of defense for protection from external substances next to the intestinal barrier. As a result, the hepatic immune system plays a central role in liver pathophysiology. Bisphenol A (BPA) is one of the most common endocrine disrupting chemicals and is primarily metabolized in the liver. Due to its ability to bind to estrogen receptors, BPA is well known to possess estrogenic activity and disrupt reproductive functions. The phase I and Phase II metabolism reactions of BPA mainly occur in the liver with the help of enzymes including cytochrome P450 (CYP), uridine 5'-diphospho-glucuronosyltransferase-glucuronosyltransferases, sulfotransferases, and glutathione-S-transferases. Although the majority of BPA is excreted after conjugation by these enzymes, untransformed BPA induces the production of reactive oxygen species through disruption of the enzymatic complex CYP, lipid accumulation, mitochondrial dysfunction, endoplasmic reticulum stress and inflammatory injury in the liver. Moreover, it has been proposed to possess a potential immunomodulatory effect. Indeed, several in vivo and in vitro studies have reported that low doses of BPA increase the population of T cells with type 1 T helper (Th1), Th2, and Th17 cells. Although the current literature lacks clear evidence on the mechanisms by which BPA is involved in T cell mediated immune responses, recent multi-omics studies suggest that it may directly interact with the antigen processing and presentation pathways. In this review, we first discuss the metabolism of BPA in the liver, before exploring currently available data on its effects on liver injury. Finally, we review its modulatory effects on the hepatic immune response, as well as potential mechanisms. By conducting this review, we aim to improve understanding on the relationship between BPA exposure and immune-related liver injury, with a focus on the antigen processing and presentation pathway and T cell-mediated response in the liver.
Collapse
Affiliation(s)
- Yoseph Asmelash Gebru
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do, 17546, Republic of Korea
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do, 17546, Republic of Korea.
| |
Collapse
|
25
|
Boni C, Rossi M, Montali I, Tiezzi C, Vecchi A, Penna A, Doselli S, Reverberi V, Ceccatelli Berti C, Montali A, Schivazappa S, Laccabue D, Missale G, Fisicaro P. What Is the Current Status of Hepatitis B Virus Viro-Immunology? Clin Liver Dis 2023; 27:819-836. [PMID: 37778772 DOI: 10.1016/j.cld.2023.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.
Collapse
Affiliation(s)
- Carolina Boni
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Vecchi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Sara Doselli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valentina Reverberi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | - Anna Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Simona Schivazappa
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Gabriele Missale
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
| |
Collapse
|
26
|
Zlotnik O, Krzywon L, Bloom J, Kalil J, Altubi I, Lazaris A, Metrakos P. Targeting Liver Metastases to Potentiate Immunotherapy in MS-Stable Colorectal Cancer-A Review of the Literature. Cancers (Basel) 2023; 15:5210. [PMID: 37958384 PMCID: PMC10649257 DOI: 10.3390/cancers15215210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 10/26/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Immunotherapy has revolutionized the treatment of several cancers, including melanoma and lung cancer. However, for colorectal cancer, it is ineffective for 95% of patients with microsatellite-stable disease. Recent evidence suggests that the liver's immune microenvironment plays a pivotal role in limiting the effectiveness of immunotherapy. There is also evidence to show that targeting liver metastases with locoregional therapies, such as surgery or irradiation, could potentiate immunotherapy for these patients. This review presents evidence from preclinical studies regarding the underlying mechanisms and from clinical studies that support this approach. Furthermore, we outline potential directions for future clinical trials. This innovative strategy could potentially establish immunotherapy as an effective treatment for MS-stable colorectal cancer patients, which are currently considered resistant.
Collapse
Affiliation(s)
- Oran Zlotnik
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Lucyna Krzywon
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
| | - Jessica Bloom
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
| | - Jennifer Kalil
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Ikhtiyar Altubi
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Anthoula Lazaris
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
| | - Peter Metrakos
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| |
Collapse
|
27
|
Ibidapo-Obe O, Bruns T. Tissue-resident and innate-like T cells in patients with advanced chronic liver disease. JHEP Rep 2023; 5:100812. [PMID: 37691689 PMCID: PMC10485156 DOI: 10.1016/j.jhepr.2023.100812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 05/07/2023] [Accepted: 05/09/2023] [Indexed: 09/12/2023] Open
Abstract
Chronic liver disease results from the orchestrated interplay of components of innate and adaptive immunity in response to liver tissue damage. Recruitment, positioning, and activation of immune cells can contribute to hepatic cell death, inflammation, and fibrogenesis. With disease progression and increasing portal pressure, repeated translocation of bacterial components from the intestinal lumen through the epithelial and vascular barriers leads to persistent mucosal, hepatic, and systemic inflammation which contributes to tissue damage, immune dysfunction, and microbial infection. It is increasingly recognised that innate-like and adaptive T-cell subsets located in the liver, mucosal surfaces, and body cavities play a critical role in the progression of advanced liver disease and inflammatory complications of cirrhosis. Mucosal-associated invariant T cells, natural killer T cells, γδ T cells, and tissue-resident memory T cells in the gut, liver, and ascitic fluid share certain characteristic features, which include that they recognise microbial products, tissue alarmins, cytokines, and stress ligands in tissues, and perform effector functions in chronic liver disease. This review highlights recent advances in the comprehension of human tissue-resident and unconventional T-cell populations and discusses the mechanisms by which they contribute to inflammation, fibrosis, immunosuppression, and antimicrobial surveillance in patients with cirrhosis. Understanding the complex interactions of immune cells in different compartments and their contribution to disease progression will provide further insights for effective diagnostic interventions and novel immunomodulatory strategies in patients with advanced chronic liver disease.
Collapse
Affiliation(s)
- Oluwatomi Ibidapo-Obe
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| |
Collapse
|
28
|
Watanabe T, Minaga K, Honjo H, Kudo M. Oral administration of ovalbumin protects mice from concanavalin A-induced hepatitis through suppression of interferon-gamma responses. Biochem Biophys Res Commun 2023; 674:117-123. [PMID: 37419032 DOI: 10.1016/j.bbrc.2023.06.091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 06/29/2023] [Indexed: 07/09/2023]
Abstract
The liver is a tolerogenic organ that exhibits hypo-responsiveness to antigens circulating in the portal vein. Antigens that are orally administered at high doses reach the liver. In our previous study, we demonstrated that administering ovalbumin (OVA) orally at high doses generates unique CD4+ T cells and tolerogenic dendritic cells, both of which can suppress T helper type 1 (Th1) responses, in the livers of two groups of mice: DO11.10 mice with transgenic CD4+ T cell receptors for OVA and BALB/c mice that received OVA-specific CD4+ T cells through adoptive transfer. This study aimed to investigate whether oral administration of OVA at high doses inhibits the development of hepatitis in the presence of OVA-specific CD4+ T cells. Oral administration of OVA at high doses inhibited the development of OVA-specific and concanavalin A (Con A)-induced hepatitis in DO11.10 mice, and these effects were associated with the downregulation of Th1 responses. Furthermore, the adoptive transfer of CD4+ T cells from the liver of OVA-fed DO11.10 mice inhibited the development of Con A-induced hepatitis in recipient BALB/c mice through the downregulation of Th1 responses. Finally, oral administration of OVA at high doses inhibited the development of Con A-induced hepatitis in BALB/c mice bearing naïve OVA-specific CD4+ T cells. These results suggest that the oral administration of antigens at high doses suppresses Th1-mediated hepatitis in an antigen-non-specific manner in the presence of antigen-specific CD4+ T cells.
Collapse
Affiliation(s)
- Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-Ku, Kyoto, 606-8507, Kyoto, Japan.
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| |
Collapse
|
29
|
Li H, Yu S, Chen L, Liu H, Shen C. Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects. Dig Dis 2023; 42:41-52. [PMID: 37729883 DOI: 10.1159/000534003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/03/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Liver transplantation (LT) is the only effective therapy for end-stage liver diseases, but some patients usually present with serious infection and immune rejection. Those with immune rejection require long-term administration of immunosuppressants, leading to serious adverse effects. Mesenchymal stem cells (MSCs) have various advantages in immune regulation and are promising drugs most likely to replace immunosuppressants. SUMMARY This study summarized the application of MSCs monotherapy, its combination with immunosuppressants, MSCs genetic modification, and MSCs derivative therapy (cell-free therapy) in LT. This may deepen the understanding of immunomodulatory role of MSCs and promote the application of MSCs in immune rejection treatment after LT. KEY MESSAGES MSCs could attenuate ischemia-reperfusion injury and immune rejection. There is no consensus on the effects of types and concentrations of immunosuppressants on MSCs. Although genetically modified MSCs have contributed to better outcomes to some extent, the best modification is still unclear. Besides, multiple clinical complications developed frequently after LT. Unfortunately, there are still few studies on the polygenic modification of MSCs for the simultaneous treatment of these complications. Therefore, more studies should be performed to investigate the potency of multi-gene modified MSCs in treating complications after LT. Additionally, MSC derivatives mainly include exosomes, extracellular vesicles, and conditioned medium. Despite therapeutic effects, these three therapies still have some limitations such as heterogeneity between generations and that they cannot be quantified accurately.
Collapse
Affiliation(s)
- Haitao Li
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Saihua Yu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Lihong Chen
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Hongzhi Liu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Conglong Shen
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| |
Collapse
|
30
|
Yang D, Zhao F, Su Y, Zhou Y, Shen J, Yu B, Zhao K, Ding Y. Integrated analysis of single-cell and bulk RNA-sequencing identifies a signature based on NK cell marker genes to predict prognosis and immunotherapy response in hepatocellular carcinoma. J Cancer Res Clin Oncol 2023; 149:10609-10621. [PMID: 37296316 DOI: 10.1007/s00432-023-04965-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023]
Abstract
BACKGROUND Prognostic modeling of NK cell marker genes in patients with hepatocellular carcinoma based on single cell sequencing and transcriptome data analysis. METHODS Marker genes of NK cells were analyzed according to single cell sequencing data of hepatocellular carcinoma. Univariate Cox regression, lasso regression analysis, and multivariate Cox regression were performed to estimate the prognostic value of NK cell marker genes. TCGA, GEO and ICGC transcriptomic data were applied to build and validate the model. Patients were divided into high and low risk groups based on the median risk score. XCELL, timer, quantitative sequences, MCP counter, EPIC, CIBERSORT and CIBERSORT-abs were performed to explore the relationship between risk score and tumor microenvironment in hepatocellular carcinoma. Finally the sensitivity of the model to chemotherapeutic agents was predicted. RESULTS Single-cell sequencing identified 207 marker genes for NK cells in hepatocellular carcinoma. Enrichment analysis suggested that NK cell marker genes were mainly involved in cellular immune function. Eight genes were selected for prognostic modeling after multifactorial COX regression analysis. The model was validated in GEO and ICGC data. Immune cell infiltration and function were higher in the low-risk group than in the high-risk group. The low-risk group was more suitable for ICI and PD-1 therapy. Half-maximal inhibitory concentrations of Sorafenib, Lapatinib, Dabrafenib, and Axitinib were significantly different on the two risk groups. CONCLUSION A new signature of hepatocyte NK cell marker genes possesses a powerful ability to predict prognosis and immunotherapeutic response in patients with hepatocellular carcinoma.
Collapse
Affiliation(s)
- Dashuai Yang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China
| | - Fangrui Zhao
- Department of Oncology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China
| | - Yang Su
- Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, 430060, Hubei, China
| | - Yu Zhou
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China
| | - Jie Shen
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China
| | - Bin Yu
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China
| | - Kailiang Zhao
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China.
| | - Youming Ding
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China.
| |
Collapse
|
31
|
Zhong X, Lv M, Ma M, Huang Q, Hu R, Li J, Yi J, Sun J, Zhou X. State of CD8 + T cells in progression from nonalcoholic steatohepatitis to hepatocellular carcinoma: From pathogenesis to immunotherapy. Biomed Pharmacother 2023; 165:115131. [PMID: 37429231 DOI: 10.1016/j.biopha.2023.115131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/26/2023] [Accepted: 07/02/2023] [Indexed: 07/12/2023] Open
Abstract
With the obesity epidemic, nonalcoholic steatohepatitis (NASH) is emerging as the fastest growing potential cause of hepatocellular carcinoma (HCC). NASH has been demonstrated to establish a tumor-prone liver microenvironment where both innate and adaptive immune systems are involved. As the most typical anti-tumor effector, the cell function of CD8+ T cells is remodeled by chronic inflammation, metabolic alteration, lipid toxicity and oxidative stress in the liver microenvironment along the NASH to HCC transition. Unexpectedly, NASH may blunt the effect of immune checkpoint inhibitor therapy against HCC due to the dysregulated CD8+ T cells. Growing evidence has supported that NASH is likely to facilitate the state transition of CD8+ T cells with changes in cell motility, effector function, metabolic reprogramming and gene transcription according to single-cell sequencing. However, the mechanistic insight of CD8+ T cell states in the NASH-driven HCC is not comprehensive. Herein, we focus on the characterization of state phenotypes of CD8+ T cells with both functional and metabolic signatures in NASH-driven fibrosis and HCC. The NASH-specific CD8+ T cells are speculated to mainly have a dualist effect, where its aberrant activated phenotype sustains chronic inflammation in NASH but subsequently triggers its exhaustion in HCC. As the exploration of CD8+ T cells on the distribution and phenotypic shifts will provide a new direction for the intervention strategies against HCC, we also discuss the implications for targeting different phenotypes of CD8+ T cells, shedding light on the personalized immunotherapy for NASH-driven HCC.
Collapse
Affiliation(s)
- Xin Zhong
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Minling Lv
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - MengQing Ma
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Qi Huang
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Rui Hu
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jing Li
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jinyu Yi
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jialing Sun
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Xiaozhou Zhou
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
| |
Collapse
|
32
|
Lin Y, Luo S, Luo M, Lu X, Li Q, Xie M, Huang Y, Liao X, Zhang Y, Li Y, Liang R. Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors. Mol Carcinog 2023; 62:1271-1283. [PMID: 37232365 DOI: 10.1002/mc.23562] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 05/03/2023] [Accepted: 05/06/2023] [Indexed: 05/27/2023]
Abstract
Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC) patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair (HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4+ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.
Collapse
Affiliation(s)
- Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Shanshan Luo
- Department of Gastrointestinal Gland Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Min Luo
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Xuerou Lu
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Qian Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Mingzhi Xie
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Yu Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Xiaoli Liao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Yumei Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China
| |
Collapse
|
33
|
Zheng W, Yang L, Jiang S, Chen M, Li J, Liu Z, Wu Z, Gong J, Chen Y. Role of Kupffer cells in tolerance induction after liver transplantation. Front Cell Dev Biol 2023; 11:1179077. [PMID: 37601106 PMCID: PMC10435084 DOI: 10.3389/fcell.2023.1179077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 07/24/2023] [Indexed: 08/22/2023] Open
Abstract
Currently, liver transplantation has reached a level of maturity where it is considered an effective treatment for end-stage liver disease and can significantly prolong the survival time of patients. However, acute and chronic rejection remain major obstacles to its efficacy. Although long-term use of immunosuppressants can prevent rejection, it is associated with serious side effects and significant economic burden for patients. Therefore, the investigation of induced immune tolerance holds crucial theoretical significance and socio-economic value. In fact, the establishment of immune tolerance in liver transplantation is intricately linked to the unique innate immune system of the liver. Kupffer cells, as a crucial component of this system, play a pivotal role in maintaining the delicate balance between inflammatory response and immune tolerance following liver transplantation. The important roles of different functions of Kupffer cells, such as phagocytosis, cell polarization, antigen presentation and cell membrane proteins, in the establishment of immune tolerance after transplantation is comprehensively summarized in this paper. Providing theoretical basis for further study and clinical application of Kupffer cells in liver transplantation.
Collapse
Affiliation(s)
- Weixiong Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lingxiang Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiming Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingxiang Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jinzheng Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zuojing Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yong Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
34
|
Terrault NA, Francoz C, Berenguer M, Charlton M, Heimbach J. Liver Transplantation 2023: Status Report, Current and Future Challenges. Clin Gastroenterol Hepatol 2023; 21:2150-2166. [PMID: 37084928 DOI: 10.1016/j.cgh.2023.04.005] [Citation(s) in RCA: 113] [Impact Index Per Article: 56.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/29/2023] [Accepted: 04/04/2023] [Indexed: 04/23/2023]
Abstract
Liver transplantation offers live-saving therapy for patients with complications of cirrhosis and stage T2 hepatocellular carcinoma. The demand for organs far outstrips the supply, and innovations aimed at increasing the number of usable deceased donors as well as alternative donor sources are a major focus. The etiologies of cirrhosis are shifting over time, with more need for transplantation among patients with alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease and less for viral hepatitis, although hepatitis B remains an important indication for transplant in countries with high endemicity. The rise in transplantation for alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease has brought attention to how patients are selected for transplantation and the strategies needed to prevent recurrent disease. In this review, we present a status report on the most pressing topics in liver transplantation and future challenges.
Collapse
Affiliation(s)
- Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California.
| | - Claire Francoz
- Liver Intensive Care and Liver Transplantation Unit, Hepatology, Hospital Beaujon, Clichy, France
| | - Marina Berenguer
- Hepatology and Liver Transplantation Unit, Hospital Universitario la Fe - IIS La Fe Valencia; CiberEHD and University of Valencia, Valencia, Spain
| | - Michael Charlton
- Transplantation Institute, University of Chicago, Chicago, Illinois
| | - Julie Heimbach
- William von Liebig Center for Transplantation, Mayo Clinic Rochester, Minnesota
| |
Collapse
|
35
|
Liu QL, Zhou H, Zhou ZG, Chen HN. Colorectal cancer liver metastasis: genomic evolution and crosstalk with the liver microenvironment. Cancer Metastasis Rev 2023; 42:575-587. [PMID: 37061644 DOI: 10.1007/s10555-023-10107-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023]
Abstract
Colorectal cancer (CRC) patients frequently develop liver metastases, which are the major cause of cancer-related mortality. The molecular basis and management of colorectal liver metastases (CRLMs) remain a challenging clinical issue. Recent genomic evidence has demonstrated the liver tropism of CRC and the presence of a stricter evolutionary bottleneck in the liver as a target organ compared to lymph nodes. This bottleneck challenging CRC cells in the liver is organ-specific and requires adaptation not only at the genetic level, but also at the phenotypic level to crosstalk with the hepatic microenvironment. Here, we highlight the emerging evidence on the clonal evolution of CRLM and review recent insights into the molecular mechanisms orchestrating the bidirectional interactions between metastatic CRC cells and the unique liver microenvironment.
Collapse
Affiliation(s)
- Qiu-Luo Liu
- Department of General Surgery, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Huijie Zhou
- Department of Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zong-Guang Zhou
- Department of General Surgery, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Hai-Ning Chen
- Department of General Surgery, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
| |
Collapse
|
36
|
Morales R, Bolarín JM, Muro M, Legaz I. Presence of KIR2DL2/S2, KIR2DL5, and KIR3DL1 Molecules in Liver Transplant Recipients with Alcoholic Cirrhosis Could Be Implicated in Death by Graft Failure. Diagnostics (Basel) 2023; 13:diagnostics13071217. [PMID: 37046435 PMCID: PMC10093628 DOI: 10.3390/diagnostics13071217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Background: The second-most frequent diagnosis among patients receiving liver transplants (LTs) is alcoholic liver disease. The multifactorial pathophysiology of alcoholic liver disease depends on the innate immune system and the inflammatory cascade. According to recent studies on these receptors, killer-cell immunoglobulin-like receptors (KIRs) may be involved in sepsis, liver rejection, and virus relapse. We aimed to investigate the impact of preclinical issues like ascites and encephalopathy and KIR genetic traits on death from sepsis, multiorgan failure (MF), and graft failure (GF) in AC patients undergoing LTs. Methods: We retrospectively reviewed 164 consecutive and deceased Caucasian AC patients who underwent LTs. Pre-transplant complications, cause of death, and patient survival were analyzed. Genomic DNA was taken from peripheral blood, and PCR-SSO was used for genotyping KIR. Results: Compared to GF patients, there was a statistically significant increase in the frequency of KIR2DL2+ (75.8% vs. 51.2%; p = 0.047). Another increase in frequency was also observed in KIR2DS2+ in sepsis compared to the GF group (51.2% vs. 43.7%; p = 0.018). In patients who passed away from MF, a decrease in KIR2DL5+ was observed in AC patients with and without encephalopathy (p = 0.018). The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.045), which was confirmed by multivariate logistic regression. The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.012) and was confirmed by multivariate logistic regression. KIR2DS1+ and KIR2DS4+ showed increased mortality due to GF compared to patients without these genes (p = 0.011 and 0.012, respectively). However, this fact was confirmed only for KIR2DS1+ by multivariate logistic Cox regression. Conclusions: The presence of the KIR2DL2/S2+, KIR2DL5+, and KIR3DL1+ genes increases the frequency of death from multiple organ failure or graft failure. Our findings highlight the AC patient’s vulnerability to a LT during hospitalization. Following the transplant and outside of it, we adopt essential preventive measures to create a routine healthcare screening to enhance and modify treatments to increase survival.
Collapse
Affiliation(s)
- Raquel Morales
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
| | - José Miguel Bolarín
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
| | - Manuel Muro
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
- Correspondence: (M.M.); (I.L.); Tel.: +34-968-369-599 (M.M.); +34-868-883-957 (I.L.); Fax: +34-968-349-678 (M.M.); +34-868-834-307 (I.L.)
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
- Correspondence: (M.M.); (I.L.); Tel.: +34-968-369-599 (M.M.); +34-868-883-957 (I.L.); Fax: +34-968-349-678 (M.M.); +34-868-834-307 (I.L.)
| |
Collapse
|
37
|
Lopez-Scarim J, Nambiar SM, Billerbeck E. Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment. Vaccines (Basel) 2023; 11:681. [PMID: 36992265 PMCID: PMC10056334 DOI: 10.3390/vaccines11030681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.
Collapse
Affiliation(s)
| | | | - Eva Billerbeck
- Division of Hepatology, Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| |
Collapse
|
38
|
Pallett LJ, Swadling L, Diniz M, Maini AA, Schwabenland M, Gasull AD, Davies J, Kucykowicz S, Skelton JK, Thomas N, Schmidt NM, Amin OE, Gill US, Stegmann KA, Burton AR, Stephenson E, Reynolds G, Whelan M, Sanchez J, de Maeyer R, Thakker C, Suveizdyte K, Uddin I, Ortega-Prieto AM, Grant C, Froghi F, Fusai G, Lens S, Pérez-Del-Pulgar S, Al-Akkad W, Mazza G, Noursadeghi M, Akbar A, Kennedy PTF, Davidson BR, Prinz M, Chain BM, Haniffa M, Gilroy DW, Dorner M, Bengsch B, Schurich A, Maini MK. Tissue CD14 +CD8 + T cells reprogrammed by myeloid cells and modulated by LPS. Nature 2023; 614:334-342. [PMID: 36697826 DOI: 10.1038/s41586-022-05645-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 12/12/2022] [Indexed: 01/26/2023]
Abstract
The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.
Collapse
Affiliation(s)
- Laura J Pallett
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
| | - Leo Swadling
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Mariana Diniz
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | | | | | | | - Jessica Davies
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Stephanie Kucykowicz
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | | | - Niclas Thomas
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Nathalie M Schmidt
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Oliver E Amin
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Upkar S Gill
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kerstin A Stegmann
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Alice R Burton
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Emily Stephenson
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Gary Reynolds
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Matt Whelan
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Jenifer Sanchez
- School of Immunology and Microbial Sciences, Kings College London, London, UK
| | - Roel de Maeyer
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Clare Thakker
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Kornelija Suveizdyte
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Imran Uddin
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | | | | | - Farid Froghi
- Division of Surgery, University College London, London, UK
| | - Giuseppe Fusai
- Division of Surgery, University College London, London, UK
| | - Sabela Lens
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Sofia Pérez-Del-Pulgar
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Walid Al-Akkad
- Institute for Liver & Digestive Health, University College London, London, UK
| | - Giuseppe Mazza
- Institute for Liver & Digestive Health, University College London, London, UK
| | - Mahdad Noursadeghi
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Arne Akbar
- Division of Medicine, University College London, London, UK
| | - Patrick T F Kennedy
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | | | - Marco Prinz
- Institute of Neuropathology, University of Freiburg, Freiburg, Germany
- Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Benjamin M Chain
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
- Department of Computer Science, University College London, London, UK
| | - Muzlifah Haniffa
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Derek W Gilroy
- Division of Medicine, University College London, London, UK
| | - Marcus Dorner
- Department of Medicine, Imperial College London, London, UK
| | - Bertram Bengsch
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany
| | - Anna Schurich
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
- School of Immunology and Microbial Sciences, Kings College London, London, UK
| | - Mala K Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
| |
Collapse
|
39
|
Sularea VM, Sugrue JA, O'Farrelly C. Innate antiviral immunity and immunometabolism in hepatocytes. Curr Opin Immunol 2023; 80:102267. [PMID: 36462263 DOI: 10.1016/j.coi.2022.102267] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 11/07/2022] [Indexed: 12/03/2022]
Abstract
The human liver mediates whole-body metabolism, systemic inflammation and responses to hepatotropic pathogens. Hepatocytes, the most abundant cell type of the liver, have critical roles in each of these activities. The regulation of metabolic pathways, such as glucose metabolism, lipid biosynthesis and oxidation, influences whole-organism functionality. However, the immune potential of the liver in general and hepatocytes in particular is also determined by metabolic ability. The major shifts in cellular metabolism required to drive activity in immune cells are now well-described. Given the unique functions of hepatocytes in systemic metabolism and inflammation, and their ability to mediate local antiviral innate immunity, the metabolic shifts required to facilitate these activities are likely to be complex and challenging to define. In this review, we explore what is known about the complex metabolic rewiring required for hepatocytes to respond appropriately to viral infection. We also discuss how viruses can manipulate hepatocyte metabolism to facilitate infection.
Collapse
Affiliation(s)
- Vasile Mihai Sularea
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Jamie A Sugrue
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; School of Medicine, Trinity College Dublin, Dublin, Ireland.
| |
Collapse
|
40
|
Abstract
Gene therapy is poised to revolutionize modern medicine, with seemingly unlimited potential for treating and curing genetic disorders. For otherwise incurable indications, including most inherited metabolic liver disorders, gene therapy provides a realistic therapeutic option. In this Review, we discuss gene supplementation and gene editing involving the use of recombinant adeno-associated virus (rAAV) vectors for the treatment of inherited liver diseases, including updates on several ongoing clinical trials that are producing promising results. Clinical testing has been essential in highlighting many key translational challenges associated with this transformative therapy. In particular, the interaction of a patient's immune system with the vector raises issues of safety and the duration of treatment efficacy. Furthermore, several serious adverse events after the administration of high doses of rAAVs suggest greater involvement of innate immune responses and pre-existing hepatic conditions than initially anticipated. Finally, permanent modification of the host genome associated with rAAV genome integration and gene editing raises concerns about the risk of oncogenicity that require careful evaluation. We summarize the main progress, challenges and pathways forward for gene therapy for liver diseases.
Collapse
|
41
|
Mei H, Wen W, Fang K, Xiong Y, Liu W, Wang J, Wan R. Immune checkpoint inhibitor-induced myocarditis and myositis in liver cancer patients: A case report and literature review. Front Oncol 2023; 12:1088659. [PMID: 36713559 PMCID: PMC9876740 DOI: 10.3389/fonc.2022.1088659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/23/2022] [Indexed: 01/13/2023] Open
Abstract
With the development of immunotherapy, immune checkpoint inhibitors (ICIs) are widely used in clinical oncology and have achieved good results. ICIs could induce immune-related adverse events (irAEs) in cancer treatment, which warrant sufficient attention. Among them, immune myositis can manifest severe symptoms affecting the whole body, and immune myocarditis occurs with a low incidence but high fatality rate. Here we report a case of grade 3/4 adverse reactions in a patient with partial hepatectomy for malignancy after using ICIs and describe the clinical presentation, laboratory results, treatment, and prognosis. It emphasizes that clinicians should focus on being alert to irAEs in liver cancer patients who have received ICI therapy. The case we present is a 56-year-old male diagnosed with hepatocellular carcinoma. Right hepatic lobectomy was performed in April 2019. Postoperative follow-up showed that transcatheter arterial chemoembolization (TACE) combined with sorafenib (400 mg twice daily) failed to stop the recurrence of the tumor. In December 2020, the patient started to use Camrelizumab injections (200mg/injection every 21 days as a cycle). After 3 cycles, the patient had decreased muscle strength in both lower extremities with chest tightness, dyspnea, and expectoration (whitish sputum). The diagnosis was ICIs injection-induced immune myocarditis and myositis accompanied. The patient's condition improved considerably by steroid pulse therapy timely. The case emphasizes that clinicians should focus on being alert to irAEs in liver cancer patients who have received ICI therapy.
Collapse
Affiliation(s)
- Haoran Mei
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wu Wen
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kang Fang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanpeng Xiong
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weiqi Liu
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jie Wang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Renhua Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China,*Correspondence: Renhua Wan,
| |
Collapse
|
42
|
Liu Z, Zhu Y, Xie H, Zou Z. Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives. Front Pharmacol 2023; 13:1077468. [PMID: 36699050 PMCID: PMC9868416 DOI: 10.3389/fphar.2022.1077468] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
In recent years, cancer immunotherapy has made remarkable achievements. Immune checkpoint inhibitors (ICIs) have been used successfully in several types of cancer in the past decade. However, expanded indication and increased use of Immune checkpoint inhibitors have resulted in increased reports of toxicity called immune-related adverse events (irAEs). Due to the unique immunological characteristics of the liver, a hepatic immune-related adverse events has also been reported, which is usually termed Immune-mediated hepatitis (IMH). So far, it is generally considered that the mechanism of IMH induced by Immune checkpoint inhibitors is mainly the overactivation of T cells. It has been reported that the incidence of IMH ranges from 1% to 15%. Because of the lack of specific markers, a diagnosis of exclusion of IMH is critical. Although most IMH is mild and recoverable, several death cases have been reported, which has been increasingly concerned. This review summarizes the current understanding of the pathophysiology, epidemiology, diagnosis, management and prognosis of IMH caused by Immune checkpoint inhibitors. It also discusses the controversial issues in IMH, such as the role of liver biopsy, grading criteria, risk factors, rational treatment strategies with steroids, and the timing of Immune checkpoint inhibitors rechallenging, which may provide helpful information for IMH in future clinical practice.
Collapse
Affiliation(s)
- Zherui Liu
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China,Medical School of Chinese PLA, Beijing, China
| | - Yun Zhu
- Medical School of Chinese PLA, Beijing, China
| | - Huan Xie
- Medical School of Chinese PLA, Beijing, China
| | - Zhengsheng Zou
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China,Medical School of Chinese PLA, Beijing, China,*Correspondence: Zhengsheng Zou,
| |
Collapse
|
43
|
Pugliese N, Alfarone L, Arcari I, Giugliano S, Parigi TL, Rescigno M, Lleo A, Aghemo A. Clinical features and management issues of NAFLD-related HCC: what we know so far. Expert Rev Gastroenterol Hepatol 2023; 17:31-43. [PMID: 36576057 DOI: 10.1080/17474124.2023.2162503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is replacing viral hepatitis as the leading cause of chronic liver disease and hepatocellular carcinoma (HCC) in many Western countries. NAFLD-associated HCC usually affects older patients with multiple comorbidities, frequently develops in the absence of cirrhosis, and is often diagnosed later with worse chance of survival. The worse prognosis is also due to limited surveillance strategies and a lower efficacy of standard treatments. AREAS COVERED We evaluate the available literature to understand the current surveillance strategies and treatment limitations in the workup of NAFLD-associated HCC, focusing on the differences with HCC associated with other liver diseases. EXPERT OPINION In this review we discuss epidemiology and risk factors for HCC in NAFLD patients and address key HCC surveillance and management issues. Although most data are still preliminary, the detection of non-cirrhotic NAFLD patients at increased risk for HCC and the potential adoption of novel screening tools could lead to accurate and suitable HCC surveillance and management strategies for NAFLD patients.
Collapse
Affiliation(s)
- Nicola Pugliese
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Ludovico Alfarone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvia Giugliano
- Laboratory of Mucosal Immunology and Microbiota, IRCCS Humanitas Research Hospital - IRCCS, via Manzoni 56, 20089 Rozzano, Italy
| | | | - Maria Rescigno
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Laboratory of Mucosal Immunology and Microbiota, IRCCS Humanitas Research Hospital - IRCCS, via Manzoni 56, 20089 Rozzano, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| |
Collapse
|
44
|
Chawla S, Das A. Preclinical-to-clinical innovations in stem cell therapies for liver regeneration. Curr Res Transl Med 2023; 71:103365. [PMID: 36427419 DOI: 10.1016/j.retram.2022.103365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/03/2022] [Accepted: 09/14/2022] [Indexed: 02/06/2023]
Abstract
Acute and chronic liver diseases are the major cause of high morbidity and mortality globally. Liver transplantation is a widely used therapeutic option for liver failure. However, the shortage of availability of liver donors has encouraged research on the alternative approach to liver regeneration. Cell-based regenerative medicine is the best alternative therapy to cater to this need. To date, advanced preclinical approaches have been undertaken on stem cell differentiation and their use in liver tissue engineering for generating efficacious and promising regenerative therapies. Advancements in the bioengineering of stem cells, and organoid generation are the way forward to efficient therapies against liver injury. This review summarizes the recent approaches for stem cell therapy-based liver regeneration and their proof of concepts for clinical application, bioengineering liver organoids to alleviate the liver failure caused due to chronic liver diseases.
Collapse
Affiliation(s)
- Shilpa Chawla
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India
| | - Amitava Das
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India.
| |
Collapse
|
45
|
Wiering L, Tacke F. Treating inflammation to combat non-alcoholic fatty liver disease. J Endocrinol 2023; 256:JOE-22-0194. [PMID: 36259984 DOI: 10.1530/joe-22-0194] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) with its more progressive form non-alcoholic steatohepatitis (NASH) has become the most common chronic liver disease, thereby representing a great burden for patients and healthcare systems. Specific pharmacological therapies for NAFLD are still missing. Inflammation is an important driver in the pathogenesis of NASH, and the mechanisms underlying inflammation in NAFLD represent possible therapeutic targets. In NASH, various intra- and extrahepatic triggers involved in the metabolic injury typically lead to the activation of different immune cells. This includes hepatic Kupffer cells, i.e. liver-resident macrophages, which can adopt an inflammatory phenotype and activate other immune cells by releasing inflammatory cytokines. As inflammation progresses, Kupffer cells are increasingly replaced by monocyte-derived macrophages with a distinct lipid-associated and scar-associated phenotype. Many other immune cells, including neutrophils, T lymphocytes - such as auto-aggressive cytotoxic as well as regulatory T cells - and innate lymphoid cells balance the progression and regression of inflammation and subsequent fibrosis. The detailed understanding of inflammatory cell subsets and their activation pathways prompted preclinical and clinical exploration of potential targets in NAFLD/NASH. These approaches to target inflammation in NASH include inhibition of immune cell recruitment via chemokine receptors (e.g. cenicriviroc), neutralization of CD44 or galectin-3 as well as agonism to nuclear factors like peroxisome proliferator-activated receptors and farnesoid X receptor that interfere with the activation of immune cells. As some of these approaches did not demonstrate convincing efficacy as monotherapies, a rational and personalized combination of therapeutic interventions may be needed for the near future.
Collapse
Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| |
Collapse
|
46
|
The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
Collapse
|
47
|
Magee N, Ahamed F, Eppler N, Jones E, Ghosh P, He L, Zhang Y. Hepatic transcriptome profiling reveals early signatures associated with disease transition from non-alcoholic steatosis to steatohepatitis. LIVER RESEARCH 2022; 6:238-250. [PMID: 36864891 PMCID: PMC9977163 DOI: 10.1016/j.livres.2022.11.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background and aim Non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease worldwide. The molecular events that influence disease progression from non-alcoholic fatty liver (NAFL) to aggressive non-alcoholic steatohepatitis (NASH) remain incompletely understood, leading to lack of mechanism-based targeted treatment options for NASH. This study aims to identify early signatures associated with disease progression from NAFL to NASH in mice and humans. Materials and methods Male C57BL/6J mice were fed a high-fat, -cholesterol, and - fructose (HFCF) diet for up to 9 months. The extent of steatosis, inflammation, and fibrosis was evaluated in liver tissues. Total RNA sequencing (RNA-seq) was conducted to determine liver transcriptomic changes. Results After being fed the HFCF diet, mice sequentially developed steatosis, early steatohepatitis, steatohepatitis with fibrosis, and eventually spontaneous liver tumor. Hepatic RNA-seq revealed that the key signatures during steatosis progression to early steatohepatitis were pathways related to extracellular matrix organization and immune responses such as T cell migration, arginine biosynthesis, C-type lectin receptor signaling, and cytokine-cytokine receptor interaction. Genes regulated by transcription factors forkhead box M1 (FOXM1) and negative elongation factor complex member E (NELFE) were significantly altered during disease progression. This phenomenon was also observed in patients with NASH. Conclusions In summary, we identified early signatures associated with disease progression from NAFL to early NASH in a mouse model that recapitulated key metabolic, histologic, and transcriptomic changes seen in humans. The findings from our study may shed light on the development of novel preventative, diagnostic, and therapeutic strategies for NASH.
Collapse
Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Forkan Ahamed
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Natalie Eppler
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Elizabeth Jones
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Priyanka Ghosh
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Lily He
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
- Liver Center, University of Kansas, Kansas City, KS, USA
| |
Collapse
|
48
|
Pallett LJ, Maini MK. Liver-resident memory T cells: life in lockdown. Semin Immunopathol 2022; 44:813-825. [PMID: 35482059 PMCID: PMC9708784 DOI: 10.1007/s00281-022-00932-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/17/2022] [Indexed: 12/15/2022]
Abstract
A subset of memory T cells has been identified in the liver with a tissue-resident profile and the capacity for long-term 'lockdown'. Here we review how they are retained in, and adapted to, the hepatic microenvironment, including its unique anatomical features and metabolic challenges. We describe potential interactions with other local cell types and the need for a better understanding of this complex bidirectional crosstalk. Pathogen or tumour antigen-specific tissue-resident memory T cells (TRM) can provide rapid frontline immune surveillance; we review the evidence for this in hepatotropic infections of major worldwide importance like hepatitis B and malaria and in liver cancers like hepatocellular carcinoma. Conversely, TRM can be triggered by pro-inflammatory and metabolic signals to mediate bystander tissue damage, with an emerging role in a number of liver pathologies. We discuss the need for liver sampling to gain a window into these compartmentalised T cells, allowing more accurate disease monitoring and future locally targeted immunotherapies.
Collapse
Affiliation(s)
- Laura J Pallett
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
| | - Mala K Maini
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
| |
Collapse
|
49
|
Dai B, Zhang R, Qi S, Liu L, Zhang X, Deng D, Zhang J, Xu Y, Liu F, Liu Z, Luo Q, Zhang Z. Intravital molecular imaging reveals that ROS-caspase-3-GSDME-induced cell punching enhances humoral immunotherapy targeting intracellular tumor antigens. Theranostics 2022; 12:7603-7623. [PMID: 36438480 PMCID: PMC9691348 DOI: 10.7150/thno.75966] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/11/2022] [Indexed: 11/24/2022] Open
Abstract
Tumor antigens (TAs)-induced humoral immune responses or TAs-specific antibodies have great application prospects for tumor therapy. However, more than half of TAs are intracellular antigens (intra-Ags) that are hardly recognized by antibodies. It is worthy to develop immunotherapeutic strategies for targeting intra-Ags. Methods: We used the far-red fluorescent protein tfRFP as an intracellular antigen to immunize mice and generated a liver metastasis model by injecting tfRFP-expressing B16 melanoma cells (tfRFP-B16) via the spleen. Intravital molecular imaging and atomic force microscopy were performed to visualize the formation of tfRFP antigen-antibody complexes (also known as immune complexes) and punched holes in cell membranes. Results: The results showed that the tfRFP-elicited immune responses inhibited the metastasis of tfRFP-expressing melanoma cells in the liver. In the circulating tfRFP-B16 tumor cells, elevated reactive oxygen species (ROS) induced slight caspase-3 activation, a probable key factor in the cleavage of gasdermin E (GSDME) proteins and punching of holes in the tumor cell membrane. Increased tumor cell membrane permeability led to the release of intra-Ag tfRFP and binding with anti-tfRFP antibodies. The formation of tfRFP antigen-antibody complexes on the membranes of tfRFP-B16 cells activated complement components to form membrane attack complexes to further destroy the cell membrane. Neutrophils were rapidly recruited, and F4/80+ macrophages phagocytized the dying tumor cells. Conclusion: The process of circulating tumor cell elimination in the tfRFP-immunized mice was triggered through the ROS-caspase-3-GSDME pathway to form intra-Ag-antibody immune complexes, which were involved in the activation of the complement system, as well as the recruitment of neutrophils and F4/80+ macrophages. An intra-Ag-elicited humoral immune response is a potent strategy for eliminating liver metastasis, which is unaffected by the liver immune tolerogenic status.
Collapse
Affiliation(s)
- Bolei Dai
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Ren Zhang
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Shuhong Qi
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Lei Liu
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Xian Zhang
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Deqiang Deng
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Jie Zhang
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Yilun Xu
- School of Biomedical Engineering, Hainan University, Haikou, Hainan 570228, China
| | - Fanxuan Liu
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Zheng Liu
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Qingming Luo
- School of Biomedical Engineering, Hainan University, Haikou, Hainan 570228, China
| | - Zhihong Zhang
- Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- School of Biomedical Engineering, Hainan University, Haikou, Hainan 570228, China
| |
Collapse
|
50
|
Fodor M, Salcher S, Gottschling H, Mair A, Blumer M, Sopper S, Ebner S, Pircher A, Oberhuber R, Wolf D, Schneeberger S, Hautz T. The liver-resident immune cell repertoire - A boon or a bane during machine perfusion? Front Immunol 2022; 13:982018. [PMID: 36311746 PMCID: PMC9609784 DOI: 10.3389/fimmu.2022.982018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.
Collapse
Affiliation(s)
- M. Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - H. Gottschling
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - M. Blumer
- Department of Anatomy and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - R. Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - D. Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: T. Hautz,
| |
Collapse
|