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Endo Y, Bekki Y, Hernandez-Alejandro R, Tomiyama K. Recent Strategies to Attenuate Hepatocellular Carcinoma Recurrence After Liver Transplantation: A Narrative Review. Cancers (Basel) 2025; 17:1650. [PMID: 40427147 PMCID: PMC12110414 DOI: 10.3390/cancers17101650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 05/03/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of liver transplant worldwide. While liver transplantation offers a survival advantage for early-stage HCC patients, post-transplant recurrence remains a significant concern, affecting up to 15% of recipients. We sought to conduct a comprehensive review related to HCC recurrence after liver transplant. Tumor-related factors such as poor differentiation, vascular invasion, and elevated tumor biomarkers like alpha-fetoprotein are key predictors of recurrence. Donor-related factors, including graft type and surgical procedures, can also influence outcomes, though their effects are less conclusive. Advancements in patient selection criteria and scoring systems, such as the Milan Criteria and RETREAT score, have improved risk stratification by incorporating tumor size, biomarkers, and response to pre-transplant treatment. Despite these measures, recurrent HCC after transplantation poses treatment challenges. Curative approaches such as resection are feasible for localized or oligometastatic recurrence and offer the best outcomes when applicable. Locoregional treatments, including ablation and transarterial chemoembolization, provide options for unresectable cases but have limited long-term efficacy. Systemic therapies, including targeted agents like sorafenib, regorafenib, and lenvatinib, have shown modest benefits in managing advanced recurrent HCC. Emerging immunotherapy approaches hold promise but face unique challenges due to the required immunosuppression in transplant recipients. Multidisciplinary evaluation remains essential for tailoring treatment plans. Future efforts should focus on refining predictive tools and exploring novel therapies to improve survival outcomes for patients with recurrent HCC after liver transplantation.
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Affiliation(s)
| | | | | | - Koji Tomiyama
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14626, USA; (Y.E.); (Y.B.); (R.H.-A.)
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Gadour E. Lesson learnt from 60 years of liver transplantation: Advancements, challenges, and future directions. World J Transplant 2025; 15:93253. [PMID: 40104199 PMCID: PMC11612893 DOI: 10.5500/wjt.v15.i1.93253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 09/06/2024] [Accepted: 09/14/2024] [Indexed: 11/26/2024] Open
Abstract
Over the past six decades, liver transplantation (LT) has evolved from an experimental procedure into a standardized and life-saving intervention, reshaping the landscape of organ transplantation. Driven by pioneering breakthroughs, technological advancements, and a deepened understanding of immunology, LT has seen remarkable progress. Some of the most notable breakthroughs in the field include advances in immunosuppression, a revised model for end-stage liver disease, and artificial intelligence (AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT, paired with ever-evolving technological advances. Additionally, the refinement of transplantation procedures, resulting in the introduction of alternative transplantation methods, such as living donor LT, split LT, and the use of marginal grafts, has addressed the challenge of organ shortage. Moreover, precision medicine, guiding personalized immunosuppressive strategies, has significantly improved patient and graft survival rates while addressing emergent issues, such as short-term complications and early allograft dysfunction, leading to a more refined strategy and enhanced post-operative recovery. Looking ahead, ongoing research explores regenerative medicine, diagnostic tools, and AI to optimize organ allocation and post-transplantation car. In summary, the past six decades have marked a transformative journey in LT with a commitment to advancing science, medicine, and patient-centered care, offering hope and extending life to individuals worldwide.
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Affiliation(s)
- Eyad Gadour
- Department of Gastroenterology and Hepatology, King Abdulaziz National Guard Hospital, Ahsa 36428, Saudi Arabia
- Internal Medicine, Zamzam University College, Khartoum 11113, Sudan
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Moeckli B, Wassmer CH, El Hajji S, Kumar R, Rodrigues Ribeiro J, Tabrizian P, Feng H, Schnickel G, Kulkarni AV, Allaire M, Asthana S, Karvellas CJ, Meeberg G, Wei L, Chouik Y, Kumar P, Gartrell RD, Martinez M, Kang E, Sogbe M, Sangro B, Schwacha-Eipper B, Schmiderer A, Krendl FJ, Goossens N, Lacotte S, Compagnon P, Toso C. Determining safe washout period for immune checkpoint inhibitors prior to liver transplantation: An international retrospective cohort study. Hepatology 2025:01515467-990000000-01187. [PMID: 40042053 DOI: 10.1097/hep.0000000000001289] [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: 11/29/2024] [Accepted: 01/28/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND AND AIMS Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced HCC patients awaiting liver transplantation (LT). However, concerns about the risk of posttransplant rejection persist. APPROACH AND RESULTS We conducted an international retrospective cohort study including 119 HCC patients who received ICIs prior to LT. We analyzed the incidence of allograft rejection, graft loss, and posttransplant recurrence with a particular focus on the washout period between the last ICI dose and LT. In this study, 24 of the 119 (20.2%) patients experienced allograft rejection with a median time to rejection of 9 days (IQR 6-10) post-LT. A linear relationship was observed between shorter washout periods and higher rejection risk. Washout periods <30 days (OR: 21.3, 95% CI: 5.93-103, p< 0.001) and between 30 and 50 days (OR: 9.48, 95% CI 2.47-46.8, p =0.002) were significantly associated with higher rejection rates in the univariate analysis compared to the washout period above 50 days. Graft loss as a result of rejection occurred in 6 patients (25%) with rejection. No factors related to grafts were associated with rejection. A longer washout period was not associated with a lower recurrence-free survival posttransplantation at 36 months (71% vs. 67%, p =0.71). CONCLUSIONS Our findings suggest that a washout period longer than 50 days for ICIs before LT appears to be safe with respect to rejection risk. While these results may help guide clinical decision-making, future prospective studies are essential to establish definitive guidelines.
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Affiliation(s)
- Beat Moeckli
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | | | - Sofia El Hajji
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Rohan Kumar
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | | | - Parissa Tabrizian
- Recanati/Miller Institute, Mount Sinai Medical Center, New York, USA
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital, Shanghai, China
| | - Gabriel Schnickel
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, University of California San Diego, San Diego, California, USA
| | | | - Manon Allaire
- AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France
| | - Sonal Asthana
- Department of Hepatobiliary Surgery and Transplantation, Aster Hospitals, Bangalore, India
| | - Constantine J Karvellas
- Faculty of Medicine and Dentistry, College of Health Sciences and School of Public Health, University of Alberta
| | - Glenda Meeberg
- Faculty of Medicine and Dentistry, College of Health Sciences and School of Public Health, University of Alberta
| | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Wuhan, China
| | - Yasmina Chouik
- Department of Hepatology, Croix-Rousse Hospital, Lyon, France
| | - Pramod Kumar
- Department of Hepatology, BGS Gleneagles Global Hospital, Bengaluru, India
| | - Robyn D Gartrell
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, USA
- Division of Pediatric Oncology, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
| | - Mercedes Martinez
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, USA
| | - Elise Kang
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, USA
| | - Miguel Sogbe
- Hepatology Unit, Department of Internal Medicine, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Bruno Sangro
- Hepatology Unit, Department of Internal Medicine, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | | | - Andreas Schmiderer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix J Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicolas Goossens
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Stephanie Lacotte
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Philippe Compagnon
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
| | - Christian Toso
- Faculty of Medicine, Department of Surgery, University of Geneva, Switzerland
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Pham JA, Coronel MM. Unlocking Transplant Tolerance with Biomaterials. Adv Healthc Mater 2025; 14:e2400965. [PMID: 38843866 PMCID: PMC11834385 DOI: 10.1002/adhm.202400965] [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: 03/14/2024] [Revised: 05/31/2024] [Indexed: 07/04/2024]
Abstract
For patients suffering from organ failure due to injury or autoimmune disease, allogeneic organ transplantation with chronic immunosuppression is considered the god standard in terms of clinical treatment. However, the true "holy grail" of transplant immunology is operational tolerance, in which the recipient exhibits a sustained lack of alloreactivity toward unencountered antigen presented by the donor graft. This outcome is resultant from critical changes to the phenotype and genotype of the immune repertoire predicated by the activation of specific signaling pathways responsive to soluble and mechanosensitive cues. Biomaterials have emerged as a medium for interfacing with and reprogramming these endogenous pathways toward tolerance in precise, minimally invasive, and spatiotemporally defined manners. By viewing seminal and contemporary breakthroughs in transplant tolerance induction through the lens of biomaterials-mediated immunomodulation strategies-which include intrinsic material immunogenicity, the depot effect, graft coatings, induction and delivery of tolerogenic immune cells, biomimicry of tolerogenic immune cells, and in situ reprogramming-this review emphasizes the stunning diversity of approaches in the field and spotlights exciting future directions for research to come.
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Affiliation(s)
- John‐Paul A. Pham
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Elizabeth Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| | - María M. Coronel
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Elizabeth Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
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Miller-Handley H, Harper G, Pham G, Turner LH, Shao TY, Russi AE, Erickson JJ, Ford ML, Araki K, Way SS. Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:192-198. [PMID: 40073258 PMCID: PMC11904129 DOI: 10.1093/jimmun/vkae007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 10/24/2024] [Indexed: 03/14/2025]
Abstract
Organ transplant recipients require continual immune-suppressive therapies to sustain allograft acceptance. Although medication nonadherence is a major cause of rejection, the mechanisms responsible for graft loss in this clinically relevant context among individuals with preceding graft acceptance remain uncertain. Here, we demonstrate that skin allograft acceptance in mice maintained with clinically relevant immune-suppressive therapies, tacrolimus and mycophenolate, sensitizes hypofunctional PD1hi graft-specific CD8+ T cells. Uninterrupted immune-suppressive therapy is required because drug discontinuation triggers allograft rejection, replicating the requirement for immune-suppressive therapy adherence in transplant recipients. Graft-specific CD8+ T cells in allograft-accepted mice show diminished effector differentiation and cytokine production, with reciprocally increased PD1 expression. Allograft acceptance-induced PD1 expression is essential, as PDL1 blockade reinvigorates graft-specific CD8+ T cell activation with ensuing allograft rejection despite continual immune-suppressive therapy. Thus, PD1 sustained CD8+ T cell inhibition is essential for allograft acceptance maintained by tacrolimus plus mycophenolate. This necessity for PD1 in sustaining allograft acceptance explains the high rates of rejection in transplant recipients with cancer administered immune checkpoint inhibitors targeting PD1/PDL1, highlighting shared immune suppression pathways exploited by tumor cells and current therapies for averting allograft rejection.
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Affiliation(s)
- Hilary Miller-Handley
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
- Department of Medicine, University of Cincinnati College of Medicine
| | - Gavin Harper
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - Giang Pham
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - Lucien H. Turner
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - Tzu-Yu Shao
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - Abigail E. Russi
- Division of Gastroenterology, Hepatology and Advanced Nutrition, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - John J. Erickson
- Division of Neonatology, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - Mandy L. Ford
- Winship Cancer Institute, Emory University School of Medicine
| | - Koichi Araki
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
| | - Sing Sing Way
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine
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Rezaee-Zavareh MS, Yeo YH, Wang T, Guo Z, Tabrizian P, Ward SC, Barakat F, Hassanein TI, Dave S, Ajmera V, Bhoori S, Mazzaferro V, Chascsa DMH, Liu MC, Aby ES, Lake JR, Sogbe M, Sangro B, Abdelrahim M, Esmail A, Schmiderer A, Chouik Y, Rudolph M, Sohal D, Giudicelli H, Allaire M, Akce M, Guadagno J, Tow CY, Massoumi H, De Simone P, Kang E, Gartrell RD, Martinez M, Paz-Fumagalli R, Toskich BB, Tran NH, Solino GA, Poltronieri Pacheco DM, Kalman RS, Agopian VG, Mehta N, Parikh ND, Singal AG, Yang JD. Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis. J Hepatol 2025; 82:107-119. [PMID: 38996924 PMCID: PMC11655254 DOI: 10.1016/j.jhep.2024.06.042] [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: 04/22/2024] [Revised: 06/05/2024] [Accepted: 06/27/2024] [Indexed: 07/14/2024]
Abstract
BACKGROUND & AIMS Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. METHODS In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS Among 91 eligible patients, with a median (IQR) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years 0.72, 95% CI 0.53-0.99, p = 0.044) and ICI washout time (aHR per 1 week 0.92, 95% CI 0.86-0.99, p = 0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p = 0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8] vs. 8.0 [9.0]; p = 0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p = 0.032). CONCLUSION Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitor use prior to liver transplantation suggest acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without immune checkpoint inhibitor exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies.
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Affiliation(s)
| | - Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA
| | - Tielong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Parissa Tabrizian
- Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY, USA
| | - Stephen C Ward
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fatma Barakat
- Southern California Liver Centers, 131 Orange Avenue, Suite 101, Coronado, CA, 92118, USA
| | - Tarek I Hassanein
- Southern California Liver Centers, 131 Orange Avenue, Suite 101, Coronado, CA, 92118, USA
| | - Shravan Dave
- Division of Gastroenterology & Hepatology, Department of Medicine, University of California, San Diego, La Jolla CA, USA
| | - Veeral Ajmera
- Division of Gastroenterology & Hepatology, Department of Medicine, University of California, San Diego, La Jolla CA, USA
| | - Sherrie Bhoori
- HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Department of Oncology, and Hemato-Oncology University of Milan, Milan, Italy
| | - David M H Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA; Transplant Center, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Margaret C Liu
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Elizabeth S Aby
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
| | - John R Lake
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
| | - Miguel Sogbe
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA; Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Internal Medicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA; Cancer Clinical Trials, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Andreas Schmiderer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Yasmina Chouik
- Cancer Research Center of Lyon (CRCL), INSERM U1052, Centre National de la Recherche Scientifique UMR5286, Lyon, France; Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Mark Rudolph
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Davendra Sohal
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Heloise Giudicelli
- AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France
| | - Manon Allaire
- AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France; INSERM UMR 1138, Centre de recherche des Cordeliers, 75006 Paris, France
| | - Mehmet Akce
- Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA
| | - Jessica Guadagno
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Clara Y Tow
- Division of Hepatology, Montefiore Medical Center, Bronx, New York; Albert Einstein College of Medicine, Bronx, NY, USA
| | - Hatef Massoumi
- Division of Hepatology, Northwell 261 East 78th Street, Floor 4, New York, NY 10075, USA
| | - Paolo De Simone
- Hepatobiliary Surgery and liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, Pisa, 56124, Italy
| | - Elise Kang
- Department of Pediatrics, Division of Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, New York, USA
| | - Robyn D Gartrell
- Department of Pediatrics, Division of Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, New York, USA; Department of Oncology, Division of Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Mercedes Martinez
- Department of Pediatrics. Vagelos College of Physician and Surgeons. Columbia University, USA
| | | | - Beau B Toskich
- Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Nguyen H Tran
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Gabriela Azevedo Solino
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória - Department of Internal Medicine - Vitória/ES - Brazil
| | - Dra Mariana Poltronieri Pacheco
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória - Department of Gastroenterology and Hepatology - Vitória/ES - Brazil
| | - Richard S Kalman
- Division of Hepatology, Department of Medicine, Einstein Healthcare Network, Philadelphia, Pennsylvania, USA
| | - Vatche G Agopian
- The Dumont-University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA.
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7
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Bansal S, Itabashi Y, Guerrero-Alba A, Fleming T, Smith MA, Bremner RM, Mohanakumar T. Regulation of cardiac allograft immune responses by microRNA-155. Transpl Immunol 2024; 87:102113. [PMID: 39222773 DOI: 10.1016/j.trim.2024.102113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/14/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION A better understanding of the immune mechanisms involved in allograft rejection after transplantation is urgently needed to improve patient outcomes. As microRNA-155 (miR155) plays a critical role in inflammation, we postulated that a deficiency of miR155 will improve cardiac allograft survival and enhance tolerance induction after heart transplantation. METHODS We developed an acute rejection mouse model through heterotopic BALB/c cardiac transplantation to C57BL/6 (wild-type) and C57BL/6 miR155 knock-out (miR155KO) mice. Further, we induced tolerance in both groups through a costimulatory blockade with CTLA4-Ig (200 μg; post-transplant day 2) and MRI antibodies (250 μg; post-transplant day 0), targeting CD28/B7 and CD40/CD154 signals, respectively. Finally, we examined the effects of injecting 100 μg of small extracellular vesicles (sEVs) isolated from wild-type mice undergoing rejection into tolerant miR155KO mice. RESULTS Mean survival time (MST) of the cardiac allografts in wild-type and miR155KO mice was 7 and 15 days, respectively (p < 0.0001). Costimulatory blockade increased MST to 65 days and > 100 days in the wild-type and miR155KO recipients, respectively (p < 0.001). Injection of sEVs isolated from wild-type mice undergoing rejection into tolerant miR155KO mice decreased the allograft survival to 9 days, significantly lower than the tolerant miR155KO mice without injection of sEVs (>100 days; p < 0.0001). CONCLUSION miR155KO mice have improved cardiac allograft survival and enhanced induction of tolerance after heterotopic cardiac transplantation. Injection of sEVs from wild-type mice undergoing rejection into the miR155KO mice reversed these benefits.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Yoshihiro Itabashi
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Alexa Guerrero-Alba
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Michael A Smith
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ross M Bremner
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - T Mohanakumar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America.
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8
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Novysedlak R, Balko J, Tavandzis J, Tovazhnianska V, Slavcev A, Vychytilova K, Smetanova J, Bohyn A, Vajter J, Borcinova M, Vanaudenaerde BM, Lischke R, Vachtenheim J, Ceulemans LJ, Ozaniak Strizova Z. Elevated PD-L1 and PECAM-1 as Diagnostic Biomarkers of Acute Rejection in Lung Transplantation. Transpl Int 2024; 37:13796. [PMID: 39640249 PMCID: PMC11617192 DOI: 10.3389/ti.2024.13796] [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: 09/12/2024] [Accepted: 11/08/2024] [Indexed: 12/07/2024]
Abstract
Acute cellular rejection (ACR) frequently occurs following lung transplantation (LuTx) and represents a risk factor for the development of chronic lung allograft dysfunction (CLAD) as well as long-term survival. The histopathological diagnosis of ACR carries a burden of interobserver variability. The widespread utilization and cost-effectiveness of immunohistochemistry (IHC) was proven beneficial in diagnosing rejection in human kidney transplantations and LuTx rat models. However, its potential for ACR detection in patients remains unexplored. We analyzed surface markers (CD3, CD4, CD8, CD20, CD68, CD47, PD-1, PD-L1, and CD31/PECAM-1) on lung tissue cryobiopsy samples collected within 6 months post-LuTx from 60 LuTx recipients, 48 of whom were diagnosed with ACR. Additionally, serum samples from 51 patients were analyzed using a multiplex bead-based Luminex assay. The cytokines and markers included PD-L1, IL2, TNFα, IFNγ, and Granzyme B. We observed a significant increase in PD-L1 tissue expression within the rejection group, suggesting a concerted effort to suppress immune responses, especially those mediated by T-cells. Furthermore, we noted significant differences in PECAM-1 levels between ACR/non-ACR. Additionally, peripheral blood C-reactive-protein levels tended to be higher in the ACR group, while Luminex serum analyses did not reveal any significant differences between groups. In conclusion, our findings suggest the potential value of PECAM-1 and PD-L1 markers in diagnosing ACR.
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Affiliation(s)
- Rene Novysedlak
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Jan Balko
- Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Janis Tavandzis
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Vira Tovazhnianska
- Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Antonij Slavcev
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Katerina Vychytilova
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Jitka Smetanova
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Alexandre Bohyn
- Department of Public Health and Primary Care, Leuven Biostatistics and Statistical Bioinformatics Center (L-BioStat), KU Leuven, Leuven, Belgium
| | - Jaromir Vajter
- Department of Anesthesiology, Resuscitation and Intensive Care Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Martina Borcinova
- Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czechia
| | - Bart M. Vanaudenaerde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Robert Lischke
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Jiri Vachtenheim
- Prague Lung Transplant Program, 3rd Department of Surgery, First Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
| | - Laurens J. Ceulemans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Zuzana Ozaniak Strizova
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia
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9
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Barbir EB, Abdulmoneim S, Dudek AZ, Kukla A. Immune Checkpoint Inhibitor Therapy for Kidney Transplant Recipients - A Review of Potential Complications and Management Strategies. Transpl Int 2024; 37:13322. [PMID: 39479217 PMCID: PMC11521864 DOI: 10.3389/ti.2024.13322] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 10/01/2024] [Indexed: 11/02/2024]
Abstract
Immune checkpoint inhibitor (ICI) therapy has enabled a paradigm shift in Oncology, with the treatment of metastatic cancer in certain tumor types becoming akin to the treatment of chronic disease. Kidney transplant recipients (KTR) are at increased risk of developing cancer compared to the general population. Historically, KTR were excluded from ICI clinical trials due to concern for allograft rejection and decreased anti-tumor efficacy. While early post-marketing data revealed an allograft rejection risk of 40%-50%, 2 recent small prospective trials have demonstrated lower rates of rejection of 0%-12%, suggesting that maintenance immunosuppression modification prior to ICI start modulates rejection risk. Moreover, objective response rates induced by ICI for the treatment of advanced or metastatic skin cancer, the most common malignancy in KTR, have been comparable to those achieved by immune intact patients. Non-invasive biomarkers may have a role in risk-stratifying patients before starting ICI, and monitoring for rejection, though allograft biopsy is required to confirm diagnosis. This clinically focused review summarizes current knowledge on complications of ICI use in KTR, including their mechanism, risk mitigation strategies, non-invasive biomarker use, approaches to treatment of rejection, and suggestions for future directions in research.
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Affiliation(s)
- Elena Bianca Barbir
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | | | - Arkadiusz Z. Dudek
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States
| | - Aleksandra Kukla
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
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10
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Ortiz V, Loeuillard E. Rethinking Immune Check Point Inhibitors Use in Liver Transplantation: Implications and Resistance. Cell Mol Gastroenterol Hepatol 2024; 19:101407. [PMID: 39326581 PMCID: PMC11609388 DOI: 10.1016/j.jcmgh.2024.101407] [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: 11/19/2023] [Revised: 09/18/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.
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Affiliation(s)
- Vivian Ortiz
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri.
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11
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Magne B, Ferland K, Savard É, Barbier MA, Morissette A, Larouche D, Beaudoin-Cloutier C, Germain L. The Human Neonatal Skin Fibroblast, an Available Cell Source for Tissue Production and Transplantation, Exhibits Low Risk of Immunogenicity In Vitro. Int J Mol Sci 2024; 25:6965. [PMID: 39000078 PMCID: PMC11241615 DOI: 10.3390/ijms25136965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/16/2024] Open
Abstract
The immunogenicity of allogeneic skin fibroblasts in transplantation has been controversial. Whether this controversy comes from a natural heterogeneity among fibroblast subsets or species-specific differences between human and mouse remains to be addressed. In this study, we sought to investigate whether fibroblasts derived from either adult or neonatal human skin tissues could induce different immune responses toward phagocytosis and T cell activation using in vitro co-culture models. Our results indicate that both phagocytosis and T cell proliferation are reduced in the presence of neonatal skin fibroblasts compared to adult skin fibroblasts. We also show that neonatal skin fibroblasts secrete paracrine factors that are responsible for reduced T cell proliferation. In addition, we show that neonatal skin fibroblasts express less class II human leukocyte antigen (HLA) molecules than adult skin fibroblasts after interferon gamma priming, which might also contribute to reduced T cell proliferation. In conclusion, this study supports the use of allogeneic neonatal skin fibroblasts as a readily available cell source for tissue production and transplantation to treat patients with severe injuries.
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Affiliation(s)
- Brice Magne
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
| | - Karel Ferland
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
| | - Étienne Savard
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
| | - Martin A. Barbier
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
| | - Amélie Morissette
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
| | - Danielle Larouche
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
| | - Chanel Beaudoin-Cloutier
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
- Burn Care Unit, CHU de Québec-Université Laval Hospital, Québec City, QC G1J 1Z4, Canada
| | - Lucie Germain
- Department of Surgery, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada
- CHU de Québec-Université Laval Research Centre, Québec City, QC G1E 6W2, Canada
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12
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Barbetta A, Rocque B, Bangerth S, Street K, Weaver C, Chopra S, Kim J, Sher L, Gaudilliere B, Akbari O, Kohli R, Emamaullee J. Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection. SCIENCE ADVANCES 2024; 10:eadm8841. [PMID: 38608023 PMCID: PMC11014454 DOI: 10.1126/sciadv.adm8841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/12/2024] [Indexed: 04/14/2024]
Abstract
Allograft rejection is common following clinical organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive. Calcineurin inhibitor dose escalation, corticosteroids, and/or lymphocyte depleting antibodies have remained the primary options for treatment of clinical rejection episodes. Here, we developed a highly multiplexed imaging mass cytometry panel to study the immune response in archival biopsies from 79 liver transplant (LT) recipients with either no rejection (NR), acute T cell-mediated rejection (TCMR), or chronic rejection (CR). This approach generated a spatially resolved proteomic atlas of 461,816 cells (42 phenotypes) derived from 96 pathologist-selected regions of interest. Our analysis revealed that regulatory (HLADR+ Treg) and PD1+ T cell phenotypes (CD4+ and CD8+ subsets), combined with variations in M2 macrophage polarization, were a unique signature of active TCMR. These data provide insights into the alloimmune microenvironment in clinical LT, including identification of potential targets for focused immunotherapy during rejection episodes and suggestion of a substantial role for immune exhaustion in TCMR.
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Affiliation(s)
- Arianna Barbetta
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Brittany Rocque
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Sarah Bangerth
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kelly Street
- Division of Biostatistics, Department of Population and Public Health, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Carly Weaver
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Shefali Chopra
- Department of Pathology, University of Southern California, Los Angeles, CA, USA
| | - Janet Kim
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Linda Sher
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Brice Gaudilliere
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- Division of Abdominal Organ Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Juliet Emamaullee
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Division of Abdominal Organ Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA, USA
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13
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Van Meerhaeghe T, Murakami N, Le Moine A, Brouard S, Sprangers B, Degauque N. Fine-tuning tumor- and allo-immunity: advances in the use of immune checkpoint inhibitors in kidney transplant recipients. Clin Kidney J 2024; 17:sfae061. [PMID: 38606169 PMCID: PMC11008728 DOI: 10.1093/ckj/sfae061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Indexed: 04/13/2024] Open
Abstract
Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.
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Affiliation(s)
- Tess Van Meerhaeghe
- Departement of Nephrology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
| | - Naoka Murakami
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, USA
- Harvard Medical School, Boston, USA
| | - Alain Le Moine
- Departement of Nephrology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Sophie Brouard
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
| | - Ben Sprangers
- Biomedical Research Institute, Department of Immunology and Infection, UHasselt, Diepenbeek, Belgium
- Department of Nephrology, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Nicolas Degauque
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
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14
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Cheng S, Wang H, Kang X, Zhang H. Immunotherapy Innovations in the Fight against Osteosarcoma: Emerging Strategies and Promising Progress. Pharmaceutics 2024; 16:251. [PMID: 38399305 PMCID: PMC10892906 DOI: 10.3390/pharmaceutics16020251] [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: 11/13/2023] [Revised: 01/20/2024] [Accepted: 01/31/2024] [Indexed: 02/25/2024] Open
Abstract
Immunosuppressive elements within the tumor microenvironment are the primary drivers of tumorigenesis and malignant advancement. The presence, as well as the crosstalk between myeloid-derived suppressor cells (MDSCs), osteosarcoma-associated macrophages (OS-Ms), regulatory T cells (Tregs), and endothelial cells (ECs) with osteosarcoma cells cause the poor prognosis of OS. In addition, the consequent immunosuppressive factors favor the loss of treatment potential. Nanoparticles offer a means to dynamically and locally manipulate immuno-nanoparticles, which present a promising strategy for transforming OS-TME. Additionally, chimeric antigen receptor (CAR) technology is effective in combating OS. This review summarizes the essential mechanisms of immunosuppressive cells in the OS-TME and the current immune-associated strategies. The last part highlights the limitations of existing therapies and offers insights into future research directions.
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Affiliation(s)
- Shigao Cheng
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Orthopedics, Hunan Loudi Central Hospital, Loudi 417000, China
| | - Huiyuan Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xuejia Kang
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Hui Zhang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
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15
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Krendl FJ, Bellotti R, Sapisochin G, Schaefer B, Tilg H, Scheidl S, Margreiter C, Schneeberger S, Oberhuber R, Maglione M. Transplant oncology - Current indications and strategies to advance the field. JHEP Rep 2024; 6:100965. [PMID: 38304238 PMCID: PMC10832300 DOI: 10.1016/j.jhepr.2023.100965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/31/2023] [Accepted: 11/04/2023] [Indexed: 02/03/2024] Open
Abstract
Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.
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Affiliation(s)
- Felix J. Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Ruben Bellotti
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Benedikt Schaefer
- Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Austria
| | - Herbert Tilg
- Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Austria
| | - Stefan Scheidl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
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16
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Kaiho T, Suzuki H, Hata A, Matsumoto H, Tanaka K, Sakairi Y, Motohashi S, Yoshino I. Targeting PD-1/PD-L1 inhibits rejection in a heterotopic tracheal allograft model of lung transplantation. Front Pharmacol 2023; 14:1298085. [PMID: 38026994 PMCID: PMC10657857 DOI: 10.3389/fphar.2023.1298085] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Immune checkpoint molecules such as programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have revolutionized the field of lung cancer treatment. As part of our study, we examined the role of these proteins in acute rejection in a mouse model of heterotopic tracheal transplantation. Recipient mice were untreated (Allo group) or treated with anti-PD-L1 (aPDL1 group) or PD-L1 Fc recombinant protein (PD-L1 Fc group). A further group of C57BL/6 mice received isografts (Iso group). The occlusion rate was significantly higher in the Allo group than in the Iso group (p = 0.0075), and also higher in the aPD-L1 group (p = 0.0066) and lower in the PD-L1 Fc group (p = 0.030) than in the Allo group. PD-L1 Fc recombinant protein treatment significantly decreased interleukin-6 and interferon-γ levels and reduced the CD4+/CD8+ T cell ratio, without increasing PD-1 and T-cell immunoglobulin mucin 3 expression in CD4+ T cells. These data suggest that PD-L1 Fc recombinant protein decreases the levels of inflammatory cytokines and the proportion of CD4+ T cells without exhaustion. The PD-L1-mediated immune checkpoint mechanism was associated with rejection in the murine tracheal transplant model, suggesting a potential novel target for immunotherapy in lung transplantation.
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Affiliation(s)
- Taisuke Kaiho
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hidemi Suzuki
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Atsushi Hata
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroki Matsumoto
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuhisa Tanaka
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuichi Sakairi
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shinichiro Motohashi
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
- Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Ichiro Yoshino
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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17
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Alghamdi S, Al-Hamoudi W. Hepatocellular Carcinoma: The Role of Immunotherapy and Transplantation in the Era of Transplant Oncology. Cancers (Basel) 2023; 15:5115. [PMID: 37958291 PMCID: PMC10648843 DOI: 10.3390/cancers15215115] [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: 08/31/2023] [Revised: 09/25/2023] [Accepted: 10/05/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. As most patients present with advanced disease, curative therapy such as surgical resection and radiofrequency ablation are rarely utilized. With the advent of immunotherapy, historical treatment approaches such as liver transplantation are being challenged. In particular, the use of immune checkpoint inhibitors (ICIs) has emerged as a safe and useful option in the treatment of HCC. However, there is concern over adverse effects, such as graft rejection and graft loss. This updated review discusses the role of immunotherapy in the pre- and post-transplantation setting and provides insights into the potential of immunotherapy as an adjunct to liver transplantation. We deliberate on the use of ICI in the setting of the Milan criteria as well as the University of California San Francisco's expanded criteria for liver transplantation. Current data suggest that ICI has utility, especially in the pretransplantation setting. Nevertheless, larger, purposefully designed clinical trials are needed to clearly identify patients who will benefit most from ICI treatment in the transplant setting and determine parameters that will minimize the risk of graft rejection and maximize the benefits of this adjunct treatment.
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Affiliation(s)
- Saad Alghamdi
- Liver & Small Bowel Health Centre Department, Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia;
| | - Waleed Al-Hamoudi
- Liver & Small Bowel Health Centre Department, Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia;
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh 11211, Saudi Arabia
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18
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Wassmer CH, El Hajji S, Papazarkadas X, Compagnon P, Tabrizian P, Lacotte S, Toso C. Immunotherapy and Liver Transplantation: A Narrative Review of Basic and Clinical Data. Cancers (Basel) 2023; 15:4574. [PMID: 37760542 PMCID: PMC10526934 DOI: 10.3390/cancers15184574] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have improved the management of patients with intermediate- and advanced-stage HCC, even making some of them potential candidates for liver transplantation. However, acute rejection has been observed after ICI therapy, challenging its safety in transplant settings. We summarize the key basic impact of immune checkpoints on HCC and liver transplantation. We analyze the available case reports and case series on the use of ICI therapy prior to and after liver transplantation. A three-month washout period is desirable between ICI therapy and liver transplantation to reduce the risk of acute rejection. Whenever possible, ICIs should be avoided after liver transplantation, and especially so early after a transplant. Globally, more robust prospective data in the field are required.
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Affiliation(s)
- Charles-Henri Wassmer
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Sofia El Hajji
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Xenofon Papazarkadas
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Philippe Compagnon
- Division of Transplantation, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland;
| | - Parissa Tabrizian
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA;
| | - Stéphanie Lacotte
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
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19
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Cesario S, Genovesi V, Salani F, Vasile E, Fornaro L, Vivaldi C, Masi G. Evolving Landscape in Liver Transplantation for Hepatocellular Carcinoma: From Stage Migration to Immunotherapy Revolution. Life (Basel) 2023; 13:1562. [PMID: 37511937 PMCID: PMC10382048 DOI: 10.3390/life13071562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/30/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Liver transplantation (LT) represents the primary curative option for HCC. Despite the extension of transplantation criteria and conversion with down-staging loco-regional treatments, transplantation is not always possible. The introduction of new standards of care in advanced HCC including a combination of immune checkpoint inhibitor-based therapies led to an improvement in response rates and could represent a promising strategy for down-staging the tumor burden. In this review, we identify reports and series, comprising a total of 43 patients who received immune checkpoint inhibitors as bridging or down-staging therapies prior to LT. Overall, treated patients registered an objective response rate of 21%, and 14 patients were reduced within the Milan criteria. Graft rejection was reported in seven patients, resulting in the death of four patients; in the remaining cases, LT was performed safely after immunotherapy. Further investigations are required to define the duration of immune checkpoint inhibitors, their minimum washout period and the LT long-term safety of this strategy. Some randomized clinical trials including immunotherapy combinations, loco-regional treatment and/or tyrosine kinase inhibitors are ongoing and will likely determine the appropriateness of immune checkpoint inhibitors' administration before LT.
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Affiliation(s)
- Silvia Cesario
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Virginia Genovesi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Francesca Salani
- Institute of Interdisciplinary Research "Health Science", Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56124 Pisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Lorenzo Fornaro
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
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20
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Barbetta A, Rocque B, Bangerth S, Street K, Weaver C, Chopra S, Kim J, Sher L, Gaudilliere B, Akbari O, Kohli R, Emamaullee J. Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection. RESEARCH SQUARE 2023:rs.3.rs-3044385. [PMID: 37461437 PMCID: PMC10350170 DOI: 10.21203/rs.3.rs-3044385/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/23/2023]
Abstract
Allograft rejection is a frequent complication following solid organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive due to the scarcity of tissue in clinical biopsy specimens. Single cell techniques have emerged as valuable tools for studying mechanisms of disease in complex tissue microenvironments. Here, we developed a highly multiplexed imaging mass cytometry panel, single cell analysis pipeline, and semi-supervised immune cell clustering algorithm to study archival biopsy specimens from 79 liver transplant (LT) recipients with histopathological diagnoses of either no rejection (NR), acute T-cell mediated rejection (TCMR), or chronic rejection (CR). This approach generated a spatially resolved proteomic atlas of 461,816 cells derived from 98 pathologist-selected regions of interest relevant to clinical diagnosis of rejection. We identified 41 distinct cell populations (32 immune and 9 parenchymal cell phenotypes) that defined key elements of the alloimmune microenvironment (AME), identified significant cell-cell interactions, and established higher order cellular neighborhoods. Our analysis revealed that both regulatory (HLA-DR+ Treg) and exhausted T-cell phenotypes (PD1+CD4+ and PD1+CD8+ T-cells), combined with variations in M2 macrophage polarization, were a unique signature of TCMR. TCMR was further characterized by alterations in cell-to-cell interactions among both exhausted immune subsets and inflammatory populations, with expansion of a CD8 enriched cellular neighborhood comprised of Treg, exhausted T-cell subsets, proliferating CD8+ T-cells, and cytotoxic T-cells. These data enabled creation of a predictive model of clinical outcomes using a subset of cell types to differentiate TCMR from NR (AUC = 0.96 ± 0.04) and TCMR from CR (AUC = 0.96 ± 0.06) with high sensitivity and specificity. Collectively, these data provide mechanistic insights into the AME in clinical LT, including a substantial role for immune exhaustion in TCMR with identification of novel targets for more focused immunotherapy in allograft rejection. Our study also offers a conceptual framework for applying spatial proteomics to study immunological diseases in archival clinical specimens.
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Affiliation(s)
| | | | | | | | | | | | | | - Linda Sher
- University of Southern California Keck School of Mdicine
| | | | - Omid Akbari
- University of Southern California, Keck School of Medicine
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21
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Valenzuela NM. JAKinibs prevent persistent, IFNγ-autonomous endothelial cell inflammation and immunogenicity. Am J Physiol Cell Physiol 2023; 325:C186-C207. [PMID: 37184230 PMCID: PMC10312316 DOI: 10.1152/ajpcell.00298.2022] [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: 07/08/2022] [Revised: 04/10/2023] [Accepted: 05/04/2023] [Indexed: 05/16/2023]
Abstract
The adhesion and subsequent activation of T cells is a critical step in local inflammatory responses, particularly of alloreactive leukocytes in rejection of transplanted donor tissue. Interferon (IFN)γ is an adaptive cytokine that promotes endothelial cell (EC) expression of pro-adhesive factors and costimulatory molecules. We recently reported that IFNγ-induced endothelial cell antigen-presenting capacity was protracted after cytokine withdrawal. This study sought to determine what intracellular signaling mediates this chronic endothelial activation by IFNγ. The durability of interferon signaling in human aortic endothelial activation was tested. Pro-adhesive and costimulatory gene expression, phenotype, secretome, and Janus kinase (JAK)/STAT phosphorylation in human primary endothelial cells were measured under chronic and transient IFNγ stimulation, with various JAK inhibitors. IFNγ reporter cells were tested for STAT1 transcriptional activity with JAK inhibition and suppressors of cytokine signaling (SOCS) overexpression, under continuous and priming conditions. The consequences of even short exposure to IFNγ were long-lasting and broad, with sustained elevation of adhesion molecules and chemokines up to 48 h later. JAK/STAT and interferon response factor expression were likewise durable, dependent on new transcription but autonomous of continuous IFNγ. Persistent STAT new transcription and JAK signaling in the endothelium was required to maintain a pro-adhesive and proimmunogenic phenotype after IFNγ withdrawal since both could be prevented by cycloheximide but only by JAKinibs with potency against JAK2. Finally, the suppressor of cytokine signaling SOCS1 failed to emerge in primed endothelial cells, which likely accounted for prolonged inflammatory gene expression. The results reveal a sustained JAK-dependent perturbation of endothelial function and suggest that JAKinibs may have therapeutic benefits in dampening vascular inflammation and allogeneic leukocyte activation.NEW & NOTEWORTHY The central question investigated in this study is why vascular endothelium remains inflamed and what underlying signaling is responsible. The new results show that the resolution of endothelial-controlled inflammation may be impaired or delayed because Janus kinase (JAK)/STAT activation is maintained autonomous of interferon (IFN)γ presence, and the late phase negative regulator suppressors of cytokine signaling (SOCS)1 fails to be induced.
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Affiliation(s)
- Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
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22
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Handelsman S, Overbey J, Chen K, Lee J, Haj D, Li Y. PD-L1's Role in Preventing Alloreactive T Cell Responses Following Hematopoietic and Organ Transplant. Cells 2023; 12:1609. [PMID: 37371079 DOI: 10.3390/cells12121609] [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: 05/02/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Over the past decade, Programmed Death-Ligand 1 (PD-L1) has emerged as a prominent target for cancer immunotherapies. However, its potential as an immunosuppressive therapy has been limited. In this review, we present the immunological basis of graft rejection and graft-versus-host disease (GVHD), followed by a summary of biologically relevant molecular interactions of both PD-L1 and Programmed Cell Death Protein 1 (PD-1). Finally, we present a translational perspective on how PD-L1 can interrupt alloreactive-driven processes to increase immune tolerance. Unlike most current therapies that block PD-L1 and/or its interaction with PD-1, this review focuses on how upregulation or reversed sequestration of this ligand may reduce autoimmunity, ameliorate GVHD, and enhance graft survival following organ transplant.
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Affiliation(s)
- Shane Handelsman
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Juliana Overbey
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Kevin Chen
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Justin Lee
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Delour Haj
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Yong Li
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
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23
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Miao X, Wu Z, Jiang Y, Liu H, Gong W. An efficient combination immunotherapy for antitumor immunity without accelerating cardiac allograft rejection. Immunology 2023; 169:157-166. [PMID: 36517459 DOI: 10.1111/imm.13618] [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: 05/23/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICIs), including antibodies against programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represents a promising systematic treatment for advanced human malignancies. Transplantation remains the ultimate therapy for end-stage organ diseases. However, the efficacy of ICI treatment in solid organ transplant (SOT) recipients remains controversial. We established a transgenic primary liver cancer mouse model and performed allogeneic heterotopic heart transplantation. Different treatments were performed and survival curves were calculated. Graft samples were collected, and immune cells and the cell surface expression of PD-L1 were analysed by flow cytometry. Inflammatory cytokine levels in the serum were measured by an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. A combination immunotherapy comprising a BET protein inhibitor (JQ1) and an immune checkpoint inhibitor (anti-PD-L1 antibody) was administered to primary liver cancer model mice bearing cardiac allografts. Interestingly, the combination immunotherapy effectively suppressed the progression of primary liver cancer but did not accelerate allograft rejection. In accordance with our previous findings, BET protein inhibition enhances the expression of a putative membrane transporter (Rab8A), which upregulates the expression of PD-L1 on the plasma membrane in a transgenic primary liver cancer mouse model. This may be a crucial mechanism of tumour progression arrest. Our data showed that heart transplantation upregulated the expression of the proinflammatory factor IFN-γ and suggested that BET protein inhibition (with JQ1) decreased PD-L1 expression in heart tissues after cardiac transplantation. This phenomenon was accompanied by enhanced infiltration of inflammatory IFN-γ. Our study provides a novel and efficient therapeutic strategy for SOT recipients.
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Affiliation(s)
- Xiaolong Miao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Zelai Wu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Yuancong Jiang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Han Liu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Weihua Gong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
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24
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Montano-Loza AJ, Rodríguez-Perálvarez ML, Pageaux GP, Sanchez-Fueyo A, Feng S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. J Hepatol 2023; 78:1199-1215. [PMID: 37208106 DOI: 10.1016/j.jhep.2023.01.030] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/30/2023] [Indexed: 05/21/2023]
Abstract
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, Córdoba, Spain; CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - George-Philippe Pageaux
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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25
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Rudolph M, Shah SA, Quillin R, Lemon K, Olowokure O, Latif T, Sohal D. Immune checkpoint inhibitors in liver transplant: a case series. J Gastrointest Oncol 2023; 14:1141-1148. [PMID: 37201081 PMCID: PMC10186520 DOI: 10.21037/jgo-22-922] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 03/02/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) in the setting of liver transplant (LT) pose a risk of rejection and hold unclear benefit in both the neoadjuvant (pre-transplant) and post-transplant salvage setting. In the pre-transplant setting, neoadjuvant ICIs may serve as a bridge to LT by downstaging disease burden to fit within transplant criteria. Outcomes in this setting include patients who had successful transplants without complications to patients who suffered severe complications, including fatal hepatic necrosis and graft failure requiring re-transplant. Some authors suggest having a period of three months between checkpoint inhibition and transplant may help mitigate adverse effects. In the post-LT setting, there are few treatment options if there is a recurrence of disease, which forces treatment teams to reconsider checkpoint inhibitors. Again, a longer period of time between transplant and checkpoint inhibition may reduce risk of rejection. Case reports of patients treated with ICIs post-transplant utilized either nivolumab or pembrolizumab. As combination atezolizumab/bevacizumab is a relatively new treatment option for unresectable hepatocellular carcinoma (HCC), there are only three reported cases using this combination in the post-LT setting. While there were no cases of rejection, all three cases had progression of disease. As immunotherapy joins transplantation as a mainstay of treatment for HCC, it remains unclear how to best navigate when the treatment course involves both immune activation and immunosuppression. CASE DESCRIPTION Patients who had an LT and were treated with ICIs (pre or post LT) at the University of Cincinnati were included in this retrospective chart review. CONCLUSIONS Fatal rejection remains a significant risk even 4 years after LT. Neoadjuvant ICIs also pose a risk for acute cellular rejection; however, this may not always be clinically significant. Graft versus host disease (GVHD) may be an additional, previously unreported risk of ICIs in the setting of LT. Prospective studies are needed to understand benefits and risks of checkpoint inhibitors in the LT setting.
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Affiliation(s)
- Mark Rudolph
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Shimul A. Shah
- Division of Transplantation, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA
| | - Ralph Quillin
- Division of Transplantation, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA
| | - Kristina Lemon
- Division of Transplantation, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA
| | - Olugbenga Olowokure
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Tahir Latif
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Davendra Sohal
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
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26
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Atallah-Yunes SA, Salman O, Robertson MJ. Post-transplant lymphoproliferative disorder: Update on treatment and novel therapies. Br J Haematol 2023; 201:383-395. [PMID: 36946218 DOI: 10.1111/bjh.18763] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/23/2023]
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk-stratified sequential algorithm with rituximab +/- chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/- RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk-stratified sequential approach. We also discuss the role of EBV-cytotoxic T lymphocytes in treatment of EBV-driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors in this population.
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Affiliation(s)
- Suheil Albert Atallah-Yunes
- Division of Hematology and Medical Oncology - Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Omar Salman
- Division of Hematology and Medical Oncology - Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Michael J Robertson
- Lymphoma Program, Division of Hematology and Medical Oncology - Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
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27
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Abboud K, Umoru G, Esmail A, Abudayyeh A, Murakami N, Al-Shamsi HO, Javle M, Saharia A, Connor AA, Kodali S, Ghobrial RM, Abdelrahim M. Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology. Cancers (Basel) 2023; 15:1433. [PMID: 36900226 PMCID: PMC10000896 DOI: 10.3390/cancers15051433] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/16/2023] [Accepted: 02/20/2023] [Indexed: 02/26/2023] Open
Abstract
The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.
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Affiliation(s)
- Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Humaid O. Al-Shamsi
- Department of Oncology, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ashish Saharia
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Ashton A. Connor
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Sudha Kodali
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Rafik M. Ghobrial
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Internal Medicine, Weill Cornell Medical College, New York, NY 14853, USA
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28
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Copic D, Direder M, Klas K, Bormann D, Laggner M, Ankersmit HJ, Mildner M. Antithymocyte Globulin Inhibits CD8 + T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. Cells 2023; 12:cells12030382. [PMID: 36766722 PMCID: PMC9913606 DOI: 10.3390/cells12030382] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/12/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. METHODS We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. FINDINGS Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. INTERPRETATION Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.
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Affiliation(s)
- Dragan Copic
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Martin Direder
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Katharina Klas
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Daniel Bormann
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Maria Laggner
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Hendrik Jan Ankersmit
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Correspondence: (H.J.A.); (M.M.); Tel.: +43-(0)1-40400-67770 (H.J.A.); +43-(0)1-40400-73507 (M.M.)
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090 Vienna, Austria
- Correspondence: (H.J.A.); (M.M.); Tel.: +43-(0)1-40400-67770 (H.J.A.); +43-(0)1-40400-73507 (M.M.)
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Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Stem Cell Transplantation: Biology and Treatment Options. J Clin Med 2022; 11:jcm11247542. [PMID: 36556158 PMCID: PMC9784583 DOI: 10.3390/jcm11247542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Post-transplant lymphoproliferative disease (PTLD) is a serious complication occurring as a consequence of immunosuppression in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) or solid organ transplantation (SOT). The majority of PTLD arises from B-cells, and Epstein-Barr virus (EBV) infection is present in 60-80% of the cases, revealing the central role played by the latent infection in the pathogenesis of the disease. Therefore, EBV serological status is considered the most important risk factor associated with PTLDs, together with the depth of T-cell immunosuppression pre- and post-transplant. However, despite the advances in pathogenesis understanding and the introduction of novel treatment options, PTLD arising after alloHSCT remains a particularly challenging disease, and there is a need for consensus on how to treat rituximab-refractory cases. This review aims to explore the pathogenesis, risk factors, and treatment options of PTLD in the alloHSCT setting, finally focusing on adoptive immunotherapy options, namely EBV-specific cytotoxic T-lymphocytes (EBV-CTL) and chimeric antigen receptor T-cells (CAR T).
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Cao W, Lu J, Li S, Song F, Xu J. Transcriptomic analysis of graft liver provides insight into the immune response of rat liver transplantation. Front Immunol 2022; 13:947437. [DOI: 10.3389/fimmu.2022.947437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022] Open
Abstract
BackgroundAs an “immune-privileged organ”, the liver has higher rates of both spontaneous tolerance and operational tolerance after being transplanted compared with other solid organs. Also, a large number of patients still need to take long-term immunosuppression regimens. Liver transplantation (LT) rejection involves varieties of pathophysiological processes and cell types, and a deeper understanding of LT immune response is urgently needed.MethodsHomogenic and allogeneic rat LT models were established, and recipient tissue was collected on postoperative day 7. The degree of LT rejection was evaluated by liver pathological changes and liver function. Differentially expressed genes (DEGs) were detected by transcriptome sequencing and confirmed by reverse transcription-polymerase chain reaction. The functional properties of DEGs were characterized by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses. The cells infiltrating the graft and recipient spleen and peripheral blood were evaluated by immunofluorescence and flow cytometry.ResultA total of 1,465 DEGs were screened, including 1,177 up-regulated genes and 288 down-regulated genes. GO enrichment and KEGG pathway analysis indicated that DEGs were involved in several immunobiological processes, including T cell activation, Th1, Th2 and Th17 cell differentiation, cytokine-cytokine receptor interaction and other immune processes. Reactome results showed that PD-1 signaling was enriched. Further research confirmed that mRNA expression of multiple immune cell markers increased and markers of T cell exhaustion significantly changed. Flow cytometry showed that the proportion of Treg decreased, and that of PD-1+CD4+ T cells and PD-1+CD8+ T cells increased in the allogeneic group.ConclusionUsing an omic approach, we revealed that the development of LT rejection involved multiple immune cells, activation of various immune pathways, and specific alterations of immune checkpoints, which would benefit risk assessment in the clinic and understanding of pathogenesis regarding LT tolerance. Further clinical validations are warranted for our findings.
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Jin X, Zhang K, Fang T, Zeng X, Yan X, Tang J, Liang Z, Xie L, Zhao D. Low-dose PD-1 inhibitor combined with lenvatinib for preemptive treatment of recurrence after liver transplantation for hepatocellular carcinoma: Case report and literature review. Front Oncol 2022; 12:951303. [PMID: 36119543 PMCID: PMC9478730 DOI: 10.3389/fonc.2022.951303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/10/2022] [Indexed: 11/18/2022] Open
Abstract
Orthotopic liver transplantation (OLT), as one of the curative methods for the treatment of hepatocellular carcinoma (HCC), has brought hope to patients with HCC. However, treatment options for HCC recurrence and metastasis after liver transplantation are limited. Immune checkpoint inhibitor (ICI), such as programmed cell death protein 1 (PD-1) inhibitor, have been successfully used in advanced or metastatic HCC, but the data on the safety of PD-1 inhibitor after liver transplantation is limited. In this article, we report a 47-year-old patient with acute-on-chronic liver failure and multiple HCC who was successfully treated with liver transplantation. On the 45th day after OLT, the patient’s alpha fetoprotein (AFP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) were increased, and imaging examination showed no residual tumor. The patient had high risk factors for tumor recurrence before operation, so the possibility of tumor recurrence was considered. When the tumor markers showed an upward trend, we immediately treated the patient with lenvatinib 8 mg, after half a month, the AFP and AFP-L3 continued to increase compared with before. Then we used low-dose nivolumab 40mg, the patient’s AFP and AFP-L3 gradually decreased. One month later, a second low-dose nivolumab 40mg was given, and the patient’s tumor markers gradually decreased to normal. No acute rejection and other complications occurred during the treatment. So far, we have followed up this patient for 2 years, and no tumor recurrence was observed. To our knowledge, this is the first reported case using a low dose of nivolumab in combination with lenvatinib to prevent recurrence of HCC after liver transplantation.
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Beenen AC, Sauerer T, Schaft N, Dörrie J. Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases. Int J Mol Sci 2022; 23:ijms23158599. [PMID: 35955729 PMCID: PMC9369208 DOI: 10.3390/ijms23158599] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 12/20/2022] Open
Abstract
Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of T cells and other effector cells. This mediates peripheral tolerance and contributes to tumor immune escape. PD-L1 became famous due to its deployment in cancer therapy, where blockage of PD-L1 with the help of therapeutic antagonistic antibodies achieved impressive clinical responses by reactivating effector cell functions against tumor cells. Therefore, in the past, the focus has been placed on PD-L1 expression and its function in various malignant cells, whereas its role in healthy tissue and diseases apart from cancer remained largely neglected. In this review, we summarize the function of PD-L1 in non-cancerous cells, outlining its discovery and origin, as well as its involvement in different cellular and immune-related processes. We provide an overview of transcriptional and translational regulation, and expression patterns of PD-L1 in different cells and organs, and illuminate the involvement of PD-L1 in different autoimmune diseases as well as in the context of transplantation and pregnancy.
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Affiliation(s)
- Amke C. Beenen
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (A.C.B.); (T.S.); (N.S.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
| | - Tatjana Sauerer
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (A.C.B.); (T.S.); (N.S.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (A.C.B.); (T.S.); (N.S.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; (A.C.B.); (T.S.); (N.S.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Ulmenweg 18, 91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-85-31127
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Luo X, Du G, Chen B, Yan G, Zhu L, Cui P, Dai H, Qi Z, Lan T. Novel immunosuppressive effect of FK506 by upregulation of PD-L1 via FKBP51 in heart transplantation. Scand J Immunol 2022; 96:e13203. [PMID: 35801698 DOI: 10.1111/sji.13203] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/13/2022] [Accepted: 07/04/2022] [Indexed: 11/30/2022]
Abstract
The calcineurin inhibitor-FK506-is a first-line immunosuppressant that regulates T-cell secretion of IL-2 and other cytokines. However, the mechanism of its protective effect on target cells and its role on tumor recurrence and interaction with anti-tumor immune checkpoint inhibitors, such as PD-L1 blocking, are still unclear. Here, in a murine heart transplantation model, we observed the upregulation of programmed death-ligand 1 (PD-L1) expression by FK506 in both dendritic cells (DCs) and allografts. Blocking PD-L1 during FK506 treatment increased IFN-γ and TNF-α expression, enhanced CD4+ and CD8+ T-cell proliferation, and suppressed Treg differentiation. Moreover, PD-L1 decreased T-cell infiltration and induced T cell apoptosis in both the spleen and graft. PD-L1 was not only required in FK506-mediated immunosuppression but also upregulated by FK506. Treatment with SAFit2, a FKBP51 selective inhibitor, reduced the expression of PD-L1 on DCs and the grafts and interfered with the immunosuppressive effect of FK506, suggesting that the mechanism depends on FK506-binding protein (FKBP) 51 expression. Overall, our results add new insights into the role of FK506, not only on T-cell cytokine secretion but also on co-inhibitory molecular regulation and target cell immune privilege.
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Affiliation(s)
- Xuewei Luo
- Medical College of Guangxi University, Nanning, China.,Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, China
| | - Guicheng Du
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, China
| | - Bingye Chen
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, China
| | - Guoliang Yan
- School of Medicine, Xiamen University, Xiamen, China
| | - Luyao Zhu
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, China
| | - Pengcheng Cui
- Medical College of Guangxi University, Nanning, China.,Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China
| | - Helong Dai
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.,Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China.,Clinical Immunology Center, Central South University, Changsha, China
| | - Zhongquan Qi
- Medical College of Guangxi University, Nanning, China.,Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, China
| | - Tianshu Lan
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, China.,Institute of Respiratory diseases，Xiamen medical college
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Losurdo G, Gravina AG, Maroni L, Gabrieletto EM, Ianiro G, Ferrarese A. Future challenges in gastroenterology and hepatology, between innovations and unmet needs: A SIGE Young Editorial Board's perspective. Dig Liver Dis 2022; 54:583-597. [PMID: 34509394 DOI: 10.1016/j.dld.2021.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 02/08/2023]
Abstract
Gastroenterology, Digestive Endoscopy and Hepatology have faced significant improvements in terms of diagnosis and therapy in the last decades. However, many fields still remain poorly explored, and many questions unanswered. Moreover, basic-science, as well as translational and clinical discoveries, together with technology advancement will determine further steps toward a better, refined care for many gastroenterological disorders in the future. Therefore, the Young Investigators of the Italian Society of Gastroenterology (SIGE) joined together, offering a perspective on major future innovations in some hot clinical topics in Gastroenterology, Endoscopy, and Hepatology, as well as the current pitfalls and the grey zones.
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Affiliation(s)
- Giuseppe Losurdo
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari; PhD Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari.
| | - Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Maroni
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy
| | | | - Gianluca Ianiro
- Digestive Disease Center, Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alberto Ferrarese
- Gastroenterology and Hepatology, Azienda Ospedaliera Universitaria Integrata, Ospedale Borgo Trento, Verona, Italy
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35
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Portuguese AJ, Tykodi SS, Blosser CD, Gooley TA, Thompson JA, Hall ET. Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review. J Natl Compr Canc Netw 2022; 20:406-416.e11. [PMID: 35390767 DOI: 10.6004/jnccn.2022.7009] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/10/2022] [Indexed: 11/17/2022]
Abstract
Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.
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Affiliation(s)
| | - Scott S Tykodi
- University of Washington.,Fred Hutchinson Cancer Research Center, and
| | | | | | - John A Thompson
- University of Washington.,Fred Hutchinson Cancer Research Center, and
| | - Evan T Hall
- University of Washington.,Fred Hutchinson Cancer Research Center, and
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Hai Nam N, Taura K, Koyama Y, Nishio T, Yamamoto G, Uemoto Y, Kimura Y, Xuefeng L, Nakamura D, Yoshino K, Ogawa E, Okamoto T, Yoshizawa A, Seo S, Iwaisako K, Yoh T, Hata K, Masui T, Okajima H, Haga H, Uemoto S, Hatano E. Increased Expressions of Programmed Death Ligand 1 and Galectin 9 in Transplant Recipients Who Achieved Tolerance After Immunosuppression Withdrawal. Liver Transpl 2022; 28:647-658. [PMID: 34655506 DOI: 10.1002/lt.26336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/27/2021] [Accepted: 10/06/2021] [Indexed: 01/13/2023]
Abstract
Programmed death 1 (PD1)/its ligand PD-L1 concomitant with T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)/its ligand galectin 9 (Gal-9) and the forkhead box P3 (FOXP3) might be involved in tolerance after liver transplantation (LT). Liver biopsies from 38 tolerant, 19 nontolerant (including 16 samples that triggered reintroduction of immunosuppression [IS] and 19 samples after IS reintroduction), and 38 control LT patients were studied. The expressions of PD1, PD-L1, Gal-9, and FOXP3 were determined by immunohistochemical and immunofluorescence (IF) staining. The success period of IS withdrawal was calculated using Kaplan-Meier curve analysis. Tolerant and control patients exhibited higher PD-L1, Gal-9, and FOXP3 levels than nontolerant patients at the moment of triggering IS reintroduction. High expressions of PD-L1 and Gal-9 were associated with prolonged success of tolerance (83.3% versus 36.7% [P < 0.01] and 73.1% versus 42.9% [P = 0.03]). A strong correlation between PD-L1 and Gal-9 expression levels was detected (Spearman r = 0.73; P ≤ 0.001), and IF demonstrated colocalization of PD-L1 and Gal-9 in the cytoplasm of hepatocytes. In conclusion, the present study demonstrated that increased expressions of PD-L1 and Gal-9 were associated with sustained tolerance after IS withdrawal in pediatric liver transplantation.
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Affiliation(s)
- Nguyen Hai Nam
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Nishio
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Gen Yamamoto
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Kimura
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Li Xuefeng
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daichi Nakamura
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenji Yoshino
- Department of Surgery, Nagahama City Hospital, Nagahama, Japan
| | - Eri Ogawa
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | | | - Satoru Seo
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
| | - Tomoaki Yoh
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshihiko Masui
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideaki Okajima
- Department of Pediatric Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University, Kyoto, Japan
| | | | - Etsuro Hatano
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Immune Checkpoint Inhibitor Therapy Before Liver Transplantation—Case and Literature Review. Transplant Direct 2022; 8:e1304. [PMID: 35310602 PMCID: PMC8923608 DOI: 10.1097/txd.0000000000001304] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/05/2022] [Accepted: 01/24/2022] [Indexed: 12/30/2022] Open
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Luo Y, Teng F, Fu H, Ding GS. Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons. World J Gastrointest Oncol 2022; 14:163-180. [PMID: 35116109 PMCID: PMC8790424 DOI: 10.4251/wjgo.v14.i1.163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/30/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has emerged as a curative strategy for hepatocellular carcinoma (HCC), but contributes to a higher predisposition to HCC recurrence in the immunosuppression context, especially for tumors beyond the Milan criteria. Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors, including HCC, it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection. Nevertheless, accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC, from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting. Generally, immunotherapy mainly includes immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and vaccine therapy. ICIs, followed by ACT, have been most investigated in LT, with some promising results. Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy, it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients. In addition, the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT. In this review, we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC. Moreover, we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.
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Affiliation(s)
- Yi Luo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Guo-Shan Ding
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
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Salcedo M, Vinaixa C, Javle M, Trapero-Marugán M, Bustamante J, Line PD. Evaluation and Management of Liver Transplant Candidates With Prior Nonhepatic Cancer: Guidelines From the ILTS/SETH Consensus Conference. Transplantation 2022; 106:e3-e11. [PMID: 34905758 DOI: 10.1097/tp.0000000000003997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Liver transplant in patients with prior nonhepatic cancer is a matter of concern, needing further research, development, and consensus guidelines. This International Liver Transplantation Society/Sociedad Española De Trasplante Hepático consensus conference document focuses on the role of liver transplantation in patients with a prior history of nonhepatic cancer. This document addresses (1) the evaluation of transplant candidates with prior cancers based on the assessment of prognosis, the natural history of individual cancers, and the emerging role for circulating DNA and minimal residual disease in these patients; (2) the impact of prior treatments, including immunotherapy for prior malignancies; and (3) the surveillance of posttransplant cancer recurrence. The consensus statement is based on previously published guidelines, as well as a review of the current, relevant, published literature.
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Affiliation(s)
- Magdalena Salcedo
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Carmen Vinaixa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Department of Hepatology and Liver Transplantation, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Milind Javle
- GI Oncology Unit, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - María Trapero-Marugán
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Unit, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Puerta de Hierro Segovia Arana IDIPHISA, Madrid, Spain
| | - Javier Bustamante
- Liver Transplant and Hepatology Unit, Cruces University Hospital, Baracaldo, Vizcaya, Spain
| | - Pål-Dag Line
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Vitale G, Gitto S, Campani C, Turco L, Baldan A, Marra F, Morelli MC. Biological therapies in patients with liver disease: are they really lifesavers? Expert Opin Biol Ther 2021; 22:473-490. [PMID: 34860629 DOI: 10.1080/14712598.2022.2013799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION The liver plays a key role in the setting of immune tolerance. Targeting antigens for presentation by antigen-presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or organs outside of the liver. Despite its non-conventional capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. Whereas chronic inflammation and intra-hepatic immuno-suppressive microenvironment occurring during liver fibrosis lead to hepatocellular carcinoma. Monoclonal antibodies have revolutionized the therapeutic strategies of many autoimmune diseases and some cancers. AREAS COVERED We review data from literature regarding the safety and efficacy of biologics in treating hepatobiliary autoimmune diseases and primary liver cancers. Furthermore, we describe their potential use in the setting of liver transplants and their main immune-related liver adverse events. EXPERT OPINION Biological therapies have changed the natural history of main autoimmune diseases and solid cancers. Compared to other organs and disease settings, the liver lags behind in biologics and their applications. The development of novel diagnostic and therapeutic strategies based on the immunological and antigenic characteristics of the hepatobiliary system could reduce mortality and transplant rates linked to chronic liver diseases.
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Affiliation(s)
- Giovanni Vitale
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Turco
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Anna Baldan
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Cristina Morelli
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Valdivia E, Rother T, Yuzefovych Y, Hack F, Wenzel N, Blasczyk R, Krezdorn N, Figueiredo C. Genetic modification of limbs using ex vivo machine perfusion. Hum Gene Ther 2021; 33:460-471. [PMID: 34779223 DOI: 10.1089/hum.2021.199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Genetic engineering is a promising tool to repair genetic disorders, improve graft function or to reduce immune responses towards the allografts. Ex vivo organ perfusion systems have the potential to mitigate ischemic-reperfusion injury, prolong preservation time or even rescue organ function. We aim to combine both technologies to develop a modular platform allowing the genetic modification of vascularized composite (VC) allografts. Rat hind limbs were perfused ex vivo under subnormothermic conditions with lentiviral vectors. Specific perfusion conditions such as controlled pressure, temperature and flow rates were optimized to support the genetic modification of the limbs. Genetic modification was detected in vascular, muscular and dermal limb tissues. Remarkably, skin follicular and interfollicular keratinocytes as well as endothelial cells (ECs) showed stable transgene expression. Furthermore, levels of injury markers such as lactate, myoglobin and lactate dehydrogenase (LDH) as well as histological analyses showed that ex vivo limb perfusion with lentiviral vectors did not cause tissue damage and limb cytokine secretion signatures were not significantly affected. The use of ex vivo VC perfusion in combination with lentiviral vectors allows an efficient and stable genetic modification of limbs representing a robust platform to genetically engineer limbs towards increasing graft survival after transplantation.
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Affiliation(s)
- Emilio Valdivia
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
| | - Tamina Rother
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
| | - Yuliia Yuzefovych
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
| | - Franziska Hack
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
| | - Nadine Wenzel
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
| | - Rainer Blasczyk
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
| | - Nicco Krezdorn
- Hannover Medical School, 9177, Clinic for Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover, Niedersachsen, Germany;
| | - Constanca Figueiredo
- Hannover Medical School, 9177, Institute of Transfusion Medicine and Transplant Engineering, Hannover, Niedersachsen, Germany;
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Borges TJ, Murakami N, Lape IT, Gassen RB, Liu K, Cai S, Daccache J, Safa K, Shimizu T, Ohori S, Paterson AM, Cravedi P, Azzi J, Sage P, Sharpe A, Li XC, Riella LV. Overexpression of PD-1 on T cells promotes tolerance in cardiac transplantation via an ICOS-dependent mechanism. JCI Insight 2021; 6:142909. [PMID: 34752418 PMCID: PMC8783692 DOI: 10.1172/jci.insight.142909] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/04/2021] [Indexed: 12/04/2022] Open
Abstract
The programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is a potent inhibitory pathway involved in immune regulation and is a potential therapeutic target in transplantation. In this study, we show that overexpression of PD-1 on T cells (PD-1 Tg) promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model when combined with costimulation blockade with CTLA-4–Ig. PD-1 overexpression on T cells also protected against chronic rejection in a single MHC II–mismatched cardiac transplant model, whereas the overexpression still allowed the generation of an effective immune response against an influenza A virus. Notably, Tregs from PD-1 Tg mice were required for tolerance induction and presented greater ICOS expression than those from WT mice. The survival benefit of PD-1 Tg recipients required ICOS signaling and donor PD-L1 expression. These results indicate that modulation of PD-1 expression, in combination with a costimulation blockade, is a promising therapeutic target to promote transplant tolerance.
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Affiliation(s)
- Thiago J Borges
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Naoka Murakami
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Isadora T Lape
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Rodrigo B Gassen
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Kaifeng Liu
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Songjie Cai
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Joe Daccache
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Kassem Safa
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Tetsunosuke Shimizu
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Shunsuke Ohori
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Alison M Paterson
- Department of Immunobiology, Harvard Medical School, Boston, United States of America
| | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America
| | - Jamil Azzi
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Peter Sage
- Transplantation Research Center, Brigham & Women's Hospital, Boston, United States of America
| | - Arlene Sharpe
- Department of Immunology, Harvard Medical School, Boston, United States of America
| | - Xian C Li
- Immunobiology and Transplant Science Center, Houston Methodist Hospital, Houston, United States of America
| | - Leonardo V Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
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Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021; 13:1267-1278. [PMID: 34754394 PMCID: PMC8554723 DOI: 10.4240/wjgs.v13.i10.1267] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/25/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is limited evidence on the safety of immunotherapy use after liver transplantation and its efficacy in treating post-liver transplant hepatocellular carcinoma (HCC) recurrence. AIM To assess the safety of immunotherapy after liver transplant and its efficacy in treating post-liver transplant HCC recurrence. METHODS A literature review was performed to identify patients with prior liver transplantation and subsequent immunotherapy. We reviewed the rejection rate and risk factors of rejection. In patients treated for HCC, the oncological outcomes were evaluated including objective response rate, progression-free survival (PFS), and overall survival (OS). RESULTS We identified 25 patients from 16 publications and 3 patients from our institutional database (total n = 28). The rejection rate was 32% (n = 9). Early mortality occurred in 21% (n = 6) and was mostly related to acute rejection (18%, n = 5). Patients who developed acute rejection were given immunotherapy earlier after transplantation (median 2.9 years vs 5.3 years, P = 0.02) and their graft biopsies might be more frequently programmed death ligand-1-positive (100% vs 33%, P = 0.053). Their PFS (1.0 ± 0.1 mo vs 3.5 ± 1.1 mo, P = 0.02) and OS (1.0 ± 0.1 mo vs 19.2 ± 5.5 mo, P = 0.001) compared inferiorly to patients without rejection. Among the 19 patients treated for HCC, the rejection rate was 32% (n = 6) and the overall objective response rate was 11%. The median PFS and OS were 2.5 ± 1.0 mo and 7.3 ± 2.7 mo after immunotherapy. CONCLUSION Rejection risk is the major obstacle to immunotherapy use in liver transplant recipients. Further studies on the potential risk factors of rejection are warranted.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021; 13:1266-1277. [DOI: 10.4240/wjgs.v13.i10.1266] [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: 02/07/2023] Open
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Feng G, Li Q, Zhu H, Jiang Y, Yuan J, Fu Y, Deng Q. Safety and Efficacy of Anti-CD19-Chimeric Antigen Receptor T Cell Combined With Programmed Cell Death 1 Inhibitor Therapy in a Patient With Refractory Post-Transplant Lymphoproliferative Disease: Case Report and Literature Review. Front Oncol 2021; 11:726134. [PMID: 34604065 PMCID: PMC8481808 DOI: 10.3389/fonc.2021.726134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Post-transplant lymphoproliferative disease (PTLD) often exhibits poor prognosis and high mortality, and there are no uniform guidelines for the treatment of this disease. Anti-CD19 chimeric antigen receptor (CAR) T cells show significant efficacy in treatment of relapse/refractory diffuse large B-cell lymphoma (DLBCL). Treatment using anti-CD19-CAR T-cell therapy in PTLD has been limited by immunosuppressants and has not been widely employed. In this study, a refractory post kidney transplant DLBCL patient with a high tumor burden was enrolled in a clinical trial of anti-CD19-CAR T-cell therapy. The tacrolimus dose was not decreased during combination chemotherapy, as the creatinine level of the patient increased. To improve the function of autologous T cells, combination therapy with anti-CD19-CAR T cells and programmed cell death 1 (PD-1) inhibitors was selected. After treatment with the combination therapy, the patient was diagnosed with grade 1 cytokine release syndrome and grade 3 immune effector cell-associated neurotoxicity syndrome. The amplification peak of anti-CD19-CAR T cells reached 9.01% on day 7. With PD-1 inhibitor maintenance therapy, his disease was maintained in partial remission for 18 weeks. However, his tumor suddenly increased in size, and he discontinued the treatment, including radiation therapy. The anti-CD19-CAR T cell and PD-1 inhibitors have a combined effect on PTLD, and this combination therapy needs to be further explored.
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Affiliation(s)
- Gang Feng
- Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Qing Li
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Haibo Zhu
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Yanyu Jiang
- Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Jijun Yuan
- Shanghai Genbase Biotechnology Co. Ltd., Shanghai, China
| | - Yingxin Fu
- Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Qi Deng
- Department of Kidney Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
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Bracamonte-Baran W, Gilotra NA, Won T, Rodriguez KM, Talor MV, Oh BC, Griffin J, Wittstein I, Sharma K, Skinner J, Johns RA, Russell SD, Anders RA, Zhu Q, Halushka MK, Brandacher G, Čiháková D. Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8 + T-Cell Infiltration After Heart Transplantation. Circ Heart Fail 2021; 14:e007982. [PMID: 34555935 PMCID: PMC8550427 DOI: 10.1161/circheartfailure.120.007982] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis. METHODS We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection. RESULTS We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1+HLA (human leukocyte antigen)-DR+ endothelial cells and CD8+ T cells (slope, -18.3 [95% CI, -35.3 to -1.3]; P=0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2Crepdl1fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls. CONCLUSIONS Loss of graft endothelial PD-L1 expression may play a role in regulating CD8+ T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.
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Affiliation(s)
- William Bracamonte-Baran
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
- Department of Medicine, Texas Tech University Health Sciences Center – Permian Basin, Odessa, TX, 79763, USA
| | - Nisha A Gilotra
- Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Taejoon Won
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Katrina M Rodriguez
- Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Monica V Talor
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Byoung C Oh
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Jan Griffin
- Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
- Current Address: Department of Medicine, Columbia University, New York, NY
| | - Ilan Wittstein
- Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Kavita Sharma
- Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - John Skinner
- Department of Anesthesiology and Critical Care Medicine, Division of Adult Anesthesia, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Roger A Johns
- Department of Anesthesiology and Critical Care Medicine, Division of Adult Anesthesia, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Stuart D Russell
- Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
- Current Address: Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Robert A Anders
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Qingfeng Zhu
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Marc K Halushka
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Daniela Čiháková
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA
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Pelizzaro F, Gambato M, Gringeri E, Vitale A, Cillo U, Farinati F, Burra P, Russo FP. Management of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers (Basel) 2021; 13:4882. [PMID: 34638365 PMCID: PMC8508053 DOI: 10.3390/cancers13194882] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/19/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10-15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Martina Gambato
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Patrizia Burra
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
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Atkinson SP. A Preview of Selected Articles. Stem Cells 2021. [DOI: 10.1002/stem.3451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Lee SK, Lee SW, Jang JW, Bae SH, Choi JY, Yoon SK. Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:10271. [PMID: 34638613 PMCID: PMC8508906 DOI: 10.3390/ijms221910271] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70-80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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Abstract
Cancer is the second leading cause of death in the worldwide. With the growing
burden of cancer, the studies on early diagnosis, treatment and prevention of
cancer are rapidly increasing. Recently, many new therapeutic strategies have
been discovered, among which immunotherapy has dramatically changed the outlook
for cancer treatment. Several clinical trials are underway around the world to
produce potential treatments. However, these trials set certain strict joining
conditions, so that the clinical data cannot be fully applied in the real world.
To help clinical oncologists with treatment decision-making, this review
collected recent studies on special populations receiving immunotherapy,
including organ transplant patients, pregnant women, pediatric patients,
patients with pulmonary tuberculosis, patients with human immunodeficiency
virus, and patients with autoimmune diseases and mental illness.
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Affiliation(s)
- Qianyun Shan
- The Second Clinical Medical College, 70571Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.,Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (lung and esophagus), Cancer Hospital of the University of Chinese Academy of Sciences (89680Zhejiang Cancer Hospital), People's Republic of China.,Department of Thoracic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), People's Republic of China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, People's Republic of China
| | - Hongyang Lu
- The Second Clinical Medical College, 70571Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.,Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (lung and esophagus), Cancer Hospital of the University of Chinese Academy of Sciences (89680Zhejiang Cancer Hospital), People's Republic of China.,Department of Thoracic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), People's Republic of China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, People's Republic of China
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