|
1
|
Bahrami P, Al Zein M, Eid AH, Sahebkar A. Liver Transplantation for Non-hepatocellular Carcinoma: The Role of Immune Checkpoint Inhibitors. J Clin Exp Hepatol 2025; 15:102558. [PMID: 40303874 PMCID: PMC12036051 DOI: 10.1016/j.jceh.2025.102558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 03/22/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC), gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), and cholangiocarcinoma (CCA) exhibit high rates of morbidity and mortality once metastasized to the liver. Liver transplantation (LT) is a viable therapeutic approach for these cancers in highly selected patients; however, their invasive nature at late stages causes many patients to be delisted from transplantation or to require further downstaging. Immunotherapy with immune checkpoint modulators has revolutionized cancer research. Immune checkpoint inhibitors (ICI) leverage the chronic inflammatory state and the overexpression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) by malignant cells and regulatory T cells, to block immune checkpoints and counteract tumor's ability to evade the immune system. However, the interaction between allograft PD-L1 and PD-1 on infiltrating T cells functions as a means of graft tolerance in cases of LT. Therefore, the application of ICIs might block this protective effect and induce graft rejection, a phenomenon particularly observed in PD-1/PD-L1 inhibiting ICIs. The risk of post-LT graft rejection can be mitigated by applying advanced biomarkers and specifying certain mutations that enhance patient selection criteria for pre-LT ICI use. Furthermore, the determination of optimal intervals of ICI administration pre- and post-LT, identification of ICI indications in de novo malignancies occurring after LT, and investigation of biomarkers for early rejection detection, pave the way for more promising LT outcomes in patients with CRC, GEP-NEN, or CCA. Therefore, this review aims to illustrate a comprehensive overview of the role of ICI therapy in the management of non-hepatocellular carcinoma transplant oncology cancers by demonstrating the potential for its application in both pre-and post-LT states, and pathways to reduce or timely detect ICI-associated graft rejection.
Collapse
Affiliation(s)
- Pegah Bahrami
- Applied Biomedical Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Al Zein
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
2
|
Xu W, Boer K, Hesselink DA, Baan CC. Extracellular Vesicles and Immune Activation in Solid Organ Transplantation: The Impact of Immunosuppression. BioDrugs 2025; 39:445-459. [PMID: 40140222 PMCID: PMC12031870 DOI: 10.1007/s40259-025-00713-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 03/28/2025]
Abstract
Recent advances in extracellular vesicle (EV) research in organ transplantation have highlighted the crucial role of donor-derived EVs in triggering alloimmune responses, ultimately contributing to transplant rejection. Following transplantation, EVs carrying donor major histocompatibility complex (MHC) molecules activate recipient antigen-presenting cells (APCs), initiating both alloreactive and regulatory T-cell responses. While immunosuppressive drugs are essential for preventing rejection, they may also influence the biogenesis and release of EVs from donor cells. This review examines the impact of maintenance immunosuppressive therapy on EV biogenesis and release post-transplantation. In addition, EV release and uptake may be influenced by specific factors such as the patient's end-stage organ disease and the transplant procedure itself. In-vitro studies using primary human parenchymal and immune cells-integrated with cutting-edge multi-omics techniques, including genomics, proteomics, lipidomics, and single-EV analysis-will offer deeper insights into EV biology and the mechanisms by which immunosuppressive agents regulate EV-initiated immune processes. A detailed understanding of how organ failure, the transplantation procedure and immunosuppressive drugs affect the biology of EVs may uncover new roles for EVs in immune activation and regulation in patients, ultimately leading to improved immunosuppressive strategies and better transplant outcomes.
Collapse
Affiliation(s)
- Weicheng Xu
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands.
| | - Karin Boer
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| |
Collapse
|
|
3
|
Li S, Li L, Weng J, He Z, Lu J, Cao W, Song F, Zhu Z, Guan B, Zhang J, Xu J. TDO2 Deficiency Exacerbates the Immune Rejection Response in Rat Liver Transplantation via the Kyn-AHR Axis. Transplantation 2025:00007890-990000000-01046. [PMID: 40164990 DOI: 10.1097/tp.0000000000005386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
BACKGROUND The role of tryptophan 2,3-dioxygenase2 (TDO2), a key enzyme in the L-tryptophan (Trp)-kynurenine (Kyn) pathway, in liver transplant immunity is unclear. This study aims to explore the role of TDO2 in liver transplant rejection. METHODS We used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to construct a TDO2 knockout rat model for liver transplant rejection. We validated the effects of TDO2 on acute rejection and survival, assessed TDO2 expression, and measured Trp and Kyn levels. We studied how TDO2 deficiency affects inflammatory cytokines, analyzed immune cell subtypes and their spatial distribution, and examined programmed death 1 and programmed cell death-ligand 1 (PDL1) spatial distribution and expression using multiplex immunohistochemistry. We also validated the regulatory mechanism of TDO2 on transplant-related immune cells in vivo and in vitro. RESULTS TDO2 deficiency in the allograft liver worsens acute rejection and reduces survival rates. During transplant rejection, TDO2 expression increases, enhancing Trp metabolism and elevating serum Kyn levels. TDO2 knockout mitigates this process. The TDO2-Kyn-aryl hydrocarbon receptor pathway regulates acute rejection. TDO2 knockout reprograms immune cell distribution, decreasing regulatory T cells and M2 macrophages in the intermediate region while increasing CD8+ T cells and M1 macrophages in the portal area, leading to M1 polarization. Additionally, TDO2 deficiency raises programmed death 1 and programmed cell death-ligand 1 expression, varying with the spatial distribution and quantity of immune cells. TDO2 can regulate the proliferation and differentiation of various immune cells through the Kyn-aryl hydrocarbon receptor pathway. CONCLUSIONS Collectively, we elucidated the mechanism of TDO2 in liver transplant immune rejection and used spatial immunity to reveal the impact of TDO2 on liver transplantation.
Collapse
Affiliation(s)
- Shanbao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junyong Weng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zeping He
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Lu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wanyue Cao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangbin Song
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhonglin Zhu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bingjie Guan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinyan Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junming Xu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Marzi L, Mega A, Turri C, Gitto S, Ferro F, Spizzo G. Immune Checkpoint Inhibitors in the Pre-Transplant Hepatocellular Carcinoma Setting: A Glimpse Beyond the Liver. Int J Mol Sci 2024; 25:11676. [PMID: 39519230 PMCID: PMC11547112 DOI: 10.3390/ijms252111676] [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: 08/26/2024] [Revised: 10/26/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. Liver transplantation (LT) is the best therapy for most patients with non-metastatic HCC. In recent years, the management of patients with HCC has considerably changed, thanks to the improvement of molecular biology knowledge and the introduction of immunotherapy. To date, systemic therapy is authorized in the Western world only in patients with advanced HCC. However, this therapy could not only stabilize the tumour disease or improve survival but could display excellent response and lead to downstaging of the tumour that finally permits LT. There are increasing reports of patients that have performed LT after pretreatment with immune checkpoint inhibitors (ICIs). However, due to the intrinsic mechanism of ICIs, graft rejection might be favoured. In addition, chronic adverse effects affecting other organs may also appear after the end of therapy. This review aims to evaluate the readiness and outcomes of LT in patients with advanced HCC who have previously undergone treatment with ICIs. It seeks to identify the challenges, risks, and benefits associated with this conversion therapy. The integration of ICIs into the treatment paradigm for advanced HCC necessitates a nuanced approach to LT. While early evidence supports the feasibility of LT following ICIs therapy, there is an urgent need for standardized guidelines and more extensive longitudinal studies to optimize patient selection, timing, and post-transplant management.
Collapse
Affiliation(s)
- Luca Marzi
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Andrea Mega
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Chiara Turri
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy;
| | - Federica Ferro
- Department of Radiology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy;
| | - Gilbert Spizzo
- Department of Internal Medicine, Oncologic Day Hospital, Hospital of Bressanone (SABES-ASDAA), 39042 Bressanone-Brixen, Italy;
| |
Collapse
|
|
6
|
Martin SP, Mehta N, Emamaullee J. Immune checkpoint inhibitors in liver transplantation: Current practice, challenges, and opportunities. Liver Transpl 2024; 30:742-752. [PMID: 38345379 DOI: 10.1097/lvt.0000000000000350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 02/08/2024] [Indexed: 06/15/2024]
Abstract
Immune checkpoint inhibitors are becoming a mainstay of cancer treatment. While first studied and approved for patients with unresectable disease, due to their efficacy, they are becoming increasingly used in the perioperative period across many cancer types. In patients with HCC, immune checkpoint inhibitors have now become the standard of care in the advanced setting and have shown promising results in the adjuvant setting after liver resection. While these drugs continue to show promise, their role in the peritransplant setting still remains a question. In this review, we explore the current use of this class of medications in patients with HCC, as well as the immunologic role of the pathways that they inhibit. We also identify potential for future research opportunities to better understand the role of these medications.
Collapse
Affiliation(s)
- Sean P Martin
- Department of Surgery, Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Department of Surgery, Division of Transplantation, Penn State Health Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Neil Mehta
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, UCSF, San Francisco, California, USA
| | - Juliet Emamaullee
- Department of Surgery, Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| |
Collapse
|
|
7
|
Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, Yi M, Xiang B. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer 2024; 23:108. [PMID: 38762484 PMCID: PMC11102195 DOI: 10.1186/s12943-024-02023-w] [Citation(s) in RCA: 130] [Impact Index Per Article: 130.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 05/10/2024] [Indexed: 05/20/2024] Open
Abstract
Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.
Collapse
Affiliation(s)
- Xin Lin
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Kuan Kang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Pan Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- FuRong Laboratory, Changsha, 410078, Hunan, China
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China
| | - Mei Yi
- Department of Dermotology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- FuRong Laboratory, Changsha, 410078, Hunan, China.
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, Hunan, China.
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China.
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
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.
Collapse
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
| |
Collapse
|
|
10
|
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.
Collapse
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
| |
Collapse
|
|
11
|
Zhang P, Wang Y, Miao Q, Chen Y. The therapeutic potential of PD-1/PD-L1 pathway on immune-related diseases: Based on the innate and adaptive immune components. Biomed Pharmacother 2023; 167:115569. [PMID: 37769390 DOI: 10.1016/j.biopha.2023.115569] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/30/2023] Open
Abstract
Currently, immunotherapy targeting programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) has revolutionized the treatment strategy of human cancer patients. Meanwhile, PD-1/PD-L1 pathway has also been implicated in the pathogenesis of many immune-related diseases, such as autoimmune diseases, chronic infection diseases and adverse pregnancy outcomes, by regulating components of the innate and adaptive immune systems. Given the power of the new therapy, a better understanding of the regulatory effects of PD-1/PD-L1 pathway on innate and adaptive immune responses in immune-related diseases will facilitate the discovery of novel biomarkers and therapeutic drug targets. Targeting this pathway may successfully halt or potentially even reverse these pathological processes. In this review, we discuss recent major advances in PD-1/PD-L1 axis regulating innate and adaptive immune components in immune-related diseases. We reveal that the impact of PD-1/PD-L1 axis on the immune system is complex and manifold and multi-strategies on the targeted PD-1/PD-L1 axis are taken in the treatment of immune-related diseases. Consequently, targeting PD-1/PD-L1 pathway, alone or in combination with other treatments, may represent a novel strategy for future therapeutic intervention on immune-related diseases.
Collapse
Affiliation(s)
- Peng Zhang
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China
| | - Yuting Wang
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China
| | - Qianru Miao
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China
| | - Ying Chen
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China.
| |
Collapse
|
|
12
|
Foy V, McNamara MG, Valle JW, Lamarca A, Edeline J, Hubner RA. Current Evidence for Immune Checkpoint Inhibition in Advanced Hepatocellular Carcinoma. Curr Oncol 2023; 30:8665-8685. [PMID: 37754543 PMCID: PMC10529518 DOI: 10.3390/curroncol30090628] [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: 08/02/2023] [Revised: 09/11/2023] [Accepted: 09/18/2023] [Indexed: 09/28/2023] Open
Abstract
The treatment of advanced unresectable HCC (aHCC) remains a clinical challenge, with limited therapeutic options and poor prognosis. The results of IMbrave150 and HIMALAYA have changed the treatment paradigm for HCC and established immune checkpoint inhibition (ICI), either combined with anti-angiogenic therapy or dual ICI, as preferred first-line therapy for eligible patients with aHCC. Numerous other combination regimens involving ICI are under investigation with the aim of improving the tumour response and survival of patients with all stages of HCC. This review will explore the current evidence for ICI in patients with advanced HCC and discuss future directions, including the unmet clinical need for predictive biomarkers to facilitate patient selection, the effects of cirrhosis aetiology on response to ICI, and the safety of its use in patients with impaired liver function.
Collapse
Affiliation(s)
- Victoria Foy
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd., Manchester M20 4BX, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd., Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd., Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd., Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
- Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Avenida de los Reyes Catolicos 2, 28040 Madrid, Spain
| | - Julien Edeline
- Centre Eugène Marquis, Av. de la Bataille Flandres Dunkerque-CS 44229, CEDEX, 35042 Rennes, France;
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd., Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
| |
Collapse
|
|
13
|
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.
Collapse
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.)
| |
Collapse
|
|
14
|
De Stefano N, Calleri A, Faini AC, Navarro-Tableros V, Martini S, Deaglio S, Patrono D, Romagnoli R. Extracellular Vesicles in Liver Transplantation: Current Evidence and Future Challenges. Int J Mol Sci 2023; 24:13547. [PMID: 37686354 PMCID: PMC10488298 DOI: 10.3390/ijms241713547] [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: 08/09/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Extracellular vesicles (EVs) are emerging as a promising field of research in liver disease. EVs are small, membrane-bound vesicles that contain various bioactive molecules, such as proteins, lipids, and nucleic acids and are involved in intercellular communication. They have been implicated in numerous physiological and pathological processes, including immune modulation and tissue repair, which make their use appealing in liver transplantation (LT). This review summarizes the current state of knowledge regarding the role of EVs in LT, including their potential use as biomarkers and therapeutic agents and their role in graft rejection. By providing a comprehensive insight into this emerging topic, this research lays the groundwork for the potential application of EVs in LT.
Collapse
Affiliation(s)
- Nicola De Stefano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy; (N.D.S.); (R.R.)
| | - Alberto Calleri
- Gastrohepatology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.); (S.M.)
| | - Angelo Corso Faini
- Immunogenetics and Transplant Biology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.F.); (S.D.)
| | - Victor Navarro-Tableros
- 2i3T, Società Per La Gestione Dell’incubatore Di Imprese e Per Il Trasferimento Tecnologico, University of Turin, 10126 Turin, Italy;
| | - Silvia Martini
- Gastrohepatology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.); (S.M.)
| | - Silvia Deaglio
- Immunogenetics and Transplant Biology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.F.); (S.D.)
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy; (N.D.S.); (R.R.)
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy; (N.D.S.); (R.R.)
| |
Collapse
|
|
15
|
Yang Zhou J, Eder D, Weber F, Heumann P, Kronenberg K, Werner JM, Geissler EK, Schlitt HJ, Hutchinson JA, Bitterer F. Case report: Predictability of clinical response and rejection risk after immune checkpoint inhibition in liver transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1211916. [PMID: 38993841 PMCID: PMC11235248 DOI: 10.3389/frtra.2023.1211916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/17/2023] [Indexed: 07/13/2024]
Abstract
Background The approval of Atezolizumab / Bevacizumab therapy (Atezo/Bev) in 2020 opened up a promising new treatment option for patients with end-stage hepatocellular carcinoma (HCC). However, liver transplant (LTx) patients with HCC are still denied this therapy owing to concerns about ICI-induced organ rejection and lack of regulatory approval. Methods A prospective observational study at a tertiary liver transplant centre monitored the compassionate, off-label use of Atezo/Bev in a single, stable LTx recipient with non-resectable HCC recurrence. Close clinical, laboratory and immunological monitoring of the patient was performed throughout a four-cycle Atezo/Bev treatment. Measured parameters were selected after a systematic review of the literature on predictive markers for clinical response and risk of graft rejection caused by ICI therapy. Results 19 articles describing 20 unique predictive biomarkers were identified. The most promising negative prognostic factors were the baseline values and dynamic course of IL-6, alpha-fetoprotein (AFP) and the AFP/CRP ratio. The frequency of regulatory T cells (Treg) reportedly correlates with the success of ICI therapy. PD-L1 and CD28 expression level with the allograft, peripheral blood CD4+ T cell numbers and Torque Teno Virus (TTV) titre may predict risk of LTx rejection following ICI therapy. No relevant side effects or acute rejection occurred during Atezo/Bev therapy; however, treatment did not prevent tumor progression. Absence of PD-L1 expression in pre-treatment liver biopsies, as well as a progressive downregulation of CD28 expression by CD4+ T cells during therapy, correctly predicted absence of rejection. Furthermore, increased IL-6 and AFP levels after starting therapy, as well as a reduction in blood Treg frequency, correctly anticipated a lack of therapeutic response. Conclusion Atezo/Bev therapy for unresectable HCC in stable LTx patients remains a controversial strategy because it carries a high-risk of rejection and therapeutic response rates are poorly defined. Although previously described biomarkers of rejection risk and therapeutic response agreed with clinical outcomes in the described case, these immunological parameters are difficult to reliably interpret. Clearly, there is an important unmet need for standardized assays and clinically validated cut-offs before we use these biomarkers to guide treatment decisions for our patients.
Collapse
Affiliation(s)
- Jordi Yang Zhou
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, University Hospital Regensburg, Regensburg, Germany
| | - Dominik Eder
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Florian Weber
- Institute for Pathology, University of Regensburg, Regensburg, Germany
| | - Philipp Heumann
- Department for Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | | | - Jens M Werner
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Edward K Geissler
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Hans J Schlitt
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Florian Bitterer
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| |
Collapse
|
|
16
|
Huang Y, Wu X, Tang S, Wu H, Nasri U, Qin Q, Song Q, Wang B, Tao H, Chong AS, Riggs AD, Zeng D. Donor programmed cell death 1 ligand 1 is required for organ transplant tolerance in major histocompatibility complex-mismatched mixed chimeras although programmed cell death 1 ligand 1 and major histocompatibility complex class II are not required for inducing chimerism. Am J Transplant 2023; 23:1116-1129. [PMID: 37105316 DOI: 10.1016/j.ajt.2023.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 04/19/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023]
Abstract
Induction of major histocompatibility complex (MHC) human leukocyte antigen (HLA)-mismatched mixed chimerism is a promising approach for organ transplantation tolerance; however, human leukocyte antigen-mismatched stable mixed chimerism has not been achieved in the clinic. Tolerogenic dendritic cell (DC) expression of MHC class II (MHC II) and programmed cell death 1 ligand 1 (PD-L1) is important for immune tolerance, but whether donor-MHC II or PD-L1 is required for the induction of stable MHC-mismatched mixed chimerism and transplant tolerance is unclear. Here, we show that a clinically applicable radiation-free regimen can establish stable MHC-mismatched mixed chimerism and organ transplant tolerance in murine models. Induction of MHC-mismatched mixed chimerism does not require donor cell expression of MHC II or PD-L1, but donor-type organ transplant tolerance in the mixed chimeras (MC) requires the donor hematopoietic cells and the organ transplants to express PD-L1. The PD-L1 expressed by donor hematopoietic cells and the programmed cell death 1 expressed by host cells augment host-type donor-reactive CD4+ and CD8+ T cell anergy/exhaustion and differentiation into peripheral regulatory T (pTreg) cells in association with the organ transplant tolerance in the MC. Conversely, host-type Treg cells augment the expansion of donor-type tolerogenic CD8+ DCs that express PD-L1. These results indicate that PD-L1 expressed by donor-type tolerogenic DCs and expansion of host-type pTreg cells in MHC-mismatched MCs play critical roles in mediating organ transplant tolerance.
Collapse
Affiliation(s)
- Yaxun Huang
- Department of Liver Transplantation, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiwei Wu
- Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Shanshan Tang
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Huiqing Wu
- Department of Pathology, City of Hope National Medical Center, Duarte, California, USA
| | - Ubaydah Nasri
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Qi Qin
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingxiao Song
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Bixin Wang
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Fujian Medical University Center of Translational Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hansen Tao
- Arthur Riggs Diabetes and Metabolism Research Institute, Summer Student Academy of City of Hope, Duarte, California, USA
| | - Anita S Chong
- The section of Transplantation, Department of Surgery, the University of Chicago, Chicago, Illinois, USA
| | - Arthur D Riggs
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Defu Zeng
- Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
| |
Collapse
|
|
17
|
Ju F, Wang D, Huang L, Jiang C, Gao C, Xiong C, Zhai G. Progress of PD-1/PD-L1 signaling in immune response to liver transplantation for hepatocellular carcinoma. Front Immunol 2023; 14:1227756. [PMID: 37545535 PMCID: PMC10399574 DOI: 10.3389/fimmu.2023.1227756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/07/2023] [Indexed: 08/08/2023] Open
Abstract
Primary liver cancer is one of the most common malignant tumors in China. The vast majority of primary liver cancer are hepatocellular carcinoma. Due to its high incidence and mortality from HCC, HCC has always been a feared type of cancer. Liver transplantation, as one of the important means to treat advanced liver cancer, has brought new hope to patients. However, as patients have been in a state of immunosuppression after liver transplantation, these patients face new problems of HCC recurrence and metastasis. A increasing number of studies have proved that blocking the PD-1/PD-L1 signaling pathway and restoring the immune killing inhibition of T cells can produce better therapeutic effects on tumors and chronic infectious diseases. As a promising treatment in the field of tumor immunotherapy, PD-1/PD-L1 inhibitors have achieved important results in liver cancer patients, but their application in liver transplantation patients is still highly controversial. This paper will introduce the mechanism of action of PD-1/PD-L1 signaling pathway and the current basic and clinical studies of PD-1/PD-L1 signaling pathway associated with immune response in HCC transplantation.
Collapse
Affiliation(s)
- Feng Ju
- Department of Laboratory Medicine, The Yangzhou University Jianhu Clinical College, Jianhu, China
| | - Dawei Wang
- Department of Infectious Diseases, The Second People’s Hospital of Yancheng City, Yancheng, China
| | - Lan Huang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Chun Jiang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Ce Gao
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Cunquan Xiong
- College of Pharmacy, Jiangsu Vocational College Medicine, Yancheng, Jiangsu, China
| | - Guanghua Zhai
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| |
Collapse
|
|
18
|
Betjes MGH, De Weerd A. Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots. Front Med (Lausanne) 2023; 10:1215167. [PMID: 37502354 PMCID: PMC10368955 DOI: 10.3389/fmed.2023.1215167] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/09/2023] [Indexed: 07/29/2023] Open
Abstract
The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.
Collapse
|
|
19
|
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.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Linda Sher
- University of Southern California Keck School of Mdicine
| | | | - Omid Akbari
- University of Southern California, Keck School of Medicine
| | | | | |
Collapse
|
|
20
|
Kuo FC, Chen CY, Lin NC, Liu C, Hsia CY, Loong CC. Optimizing the Safe Washout Period for Liver Transplantation Following Immune Checkpoint Inhibitors with Atezolizumab, Nivolumab, or Pembrolizumab. Transplant Proc 2023:S0041-1345(23)00232-4. [PMID: 37127513 DOI: 10.1016/j.transproceed.2023.03.064] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 03/28/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND Using immune checkpoint inhibitors (ICIs) as a downstaging therapy for liver transplantation (LT) has improved outcomes for patients with advanced hepatocellular carcinoma (HCC). However, this therapy carries a risk of post-transplant graft rejection. The washout (WO) period between the last ICI dose and LT seems critical in preventing postoperative rejection. This study aimed to optimize the WO period by balancing tumor burden suppression and rejection prevention using ICIs before LT. METHODS We reviewed published case reports or series from March 2020 to December 2022 regarding LT for HCC after downstaging or bridge therapy with ICIs and included 4 of our cases. Most patients received atezolizumab, nivolumab, or pembrolizumab; these ICIs shared a half-life of around 28 days. Therefore, we excluded cases without definite WO period data and those using non-atezolizumab/nivolumab/pembrolizumab ICIs and ultimately enrolled 22 patients for analysis. We compared their clinical outcomes and estimated the rejection-free survival for every 0.5 half-life interval. RESULTS Most study subjects received nivolumab (n = 25). Six patients had severe rejections (nivolumab group, n = 5) and needed rescue management. Of the 6 cases, 1 patient died after rejection, and 2 underwent re-transplantation. The median WO period in these 6 patients was 22 days (IQR: 9-35 days). In addition, we found that a 1.5 half-life (42 days) was the shortest safe WO period associated with significant rejection-free survival (P = .005). CONCLUSIONS Our results showed that 42 days was the safest WO period before LT for HCC after ICI with atezolizumab, nivolumab, or pembrolizumab.
Collapse
Affiliation(s)
- Fang-Cheng Kuo
- Division of Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Cheng-Yen Chen
- Division of Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Niang-Cheng Lin
- Division of Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chinsu Liu
- Division of Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Cheng-Yuan Hsia
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Che-Chuan Loong
- Division of Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| |
Collapse
|
|
21
|
Cui X, Yan C, Xu Y, Li D, Guo M, Sun L, Zhu Z. Allograft rejection following immune checkpoint inhibitors in solid organ transplant recipients: A safety analysis from a literature review and a pharmacovigilance system. Cancer Med 2023; 12:5181-5194. [PMID: 36504294 PMCID: PMC10028127 DOI: 10.1002/cam4.5394] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/13/2022] [Accepted: 10/21/2022] [Indexed: 12/14/2022] Open
Abstract
AIM This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). METHODS Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. RESULTS A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025 : 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. CONCLUSION Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.
Collapse
Affiliation(s)
- Xiangli Cui
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cilin Yan
- School of Automation Science and Electrical Engineering, Beihang University, Beijing, China
| | - Ye Xu
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dandan Li
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mingxing Guo
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Liying Sun
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhijun Zhu
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
22
|
Laschtowitz A, Roderburg C, Tacke F, Mohr R. Preoperative Immunotherapy in Hepatocellular Carcinoma: Current State of the Art. J Hepatocell Carcinoma 2023; 10:181-191. [PMID: 36789252 PMCID: PMC9922501 DOI: 10.2147/jhc.s347944] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 02/01/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy that requires multidisciplinary evaluation to develop individualized and tailored treatment concepts. While liver resection and transplantation represent the mainstay of curative treatment in patients with early-stage HCC, disease recurrence remains an important burden. Immune checkpoint inhibitors (ICI) have become standard of care in the palliative setting, achieving promising response rates with overall good tolerability. Accordingly, ICIs are being evaluated in (neo)adjuvant concepts in order to improve survival. Nevertheless, neoadjuvant therapies are not recommended by current guidelines as they have not been proven to improve the outcome in large Phase III trials yet. Especially in the context of liver transplantation (LT), perioperative ICI usage is in need of a particularly critical risk-benefit assessment, as the immunotherapy may significantly increase the risk of rejection. In this review, we summarize available data on ICI-based perioperative treatment strategies in HCC. We discuss current drawbacks and challenges of this treatment concept and specifically highlight the risk of allograft rejection when ICI are given in patients (subsequently) considered for liver transplantation.
Collapse
Affiliation(s)
- Alena Laschtowitz
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany,Correspondence: Raphael Mohr, Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany, Email
| |
Collapse
|
|
23
|
Immunopathological insights into villitis of unknown etiology on the basis of transplant immunology. Placenta 2023; 131:49-57. [PMID: 36473393 DOI: 10.1016/j.placenta.2022.11.003] [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: 07/22/2022] [Accepted: 11/15/2022] [Indexed: 11/27/2022]
Abstract
Villitis of unknown etiology (VUE) is an inflammatory disease characterized by the infiltration of maternal CD8 +T cells into the placental villi. Although the pathogenesis of VUE is still debated, dysregulation of the immune system appears to be an important factor in the development of the disease. Interaction of maternal T cells with the fetal antigens seems to be the trigger for the VUE onset. In this context, graft vs host disease (GVHD) and allographic rejection seem to share similarities in the VUE immunopathological mechanism, especially those related to immunoregulation. In this review, we compared the immunological characteristics of VUE with allograft rejection, and GVHD favoring a better knowledge of VUE pathogenesis that may contribute to VUE therapeutics strategies in the future.
Collapse
|
|
24
|
Luo Z, Liao T, Zhang Y, Zheng H, Sun Q, Han F, Ma M, Ye Y, Sun Q. Ex vivo anchored PD-L1 functionally prevent in vivo renal allograft rejection. Bioeng Transl Med 2022; 7:e10316. [PMID: 36176616 PMCID: PMC9472007 DOI: 10.1002/btm2.10316] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 11/09/2022] Open
Abstract
Organ transplantation is the optimal treatment for patients with end-stage diseases. T cell activation is a major contributing factor toward the trigger of rejection. Induction therapy with T cell depleting agent is a common option but increases the risk of severe systemic infections. The ideal therapy should precisely target the allograft. Here, we developed a membrane-anchored-protein PD-L1 (map-PD-L1), which effectively anchored onto the surface of rat glomerular endothelial cells (rgEC). The expression of PD-L1 increased directly with map-PD-L1 concentration and incubation time. Moreover, map-PD-L1 was even stably anchored to rgEC at low temperature. Map-PD-L1 could bind to PD-1 and significantly promote T cell apoptosis and inhibited T cell activation. Using kidney transplantation models, we found that ex vivo perfusion of donor kidneys with map-PD-L1 significantly protected grafts against acute injury without using any immunosuppressant. We found map-PD-L1 could reduce T cell graft infiltration and increase intragraft Treg infiltration, suggesting a long-term effect in allograft protection. More importantly, modifying donor organs in vitro was not only safe, but also significantly reduced the side effects of systemic application. Our results suggested that ex vivo perfusion of donor organ with map-PD-L1 might provide a viable clinical option for organ-targeted induction therapy in organ transplantation.
Collapse
Affiliation(s)
- Zihuan Luo
- Department of Renal TransplantationGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Tao Liao
- Department of Renal TransplantationGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yannan Zhang
- Department of Renal TransplantationGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Haofeng Zheng
- Department of Renal TransplantationGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Qipeng Sun
- Department of Renal TransplantationGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Fei Han
- Organ Transplantation Research InstituteThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Maolin Ma
- Organ Transplantation Research InstituteThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Yongrong Ye
- Organ Transplantation Research InstituteThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Qiquan Sun
- Department of Renal TransplantationGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhouGuangdongChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| |
Collapse
|
|
25
|
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.
Collapse
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
| |
Collapse
|
|
26
|
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
|
|
27
|
Halma J, Pierce S, McLennan R, Bradley T, Fischer R. Natural killer cells in liver transplantation: Can we harness the power of the immune checkpoint to promote tolerance? Clin Transl Sci 2021; 15:1091-1103. [PMID: 34866338 PMCID: PMC9099129 DOI: 10.1111/cts.13208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 08/30/2021] [Accepted: 11/14/2021] [Indexed: 11/29/2022] Open
Abstract
The roles that natural killer (NK) cells play in liver disease and transplantation remain ill‐defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes, such as receptor protein expression and function differ among species, make study of primate or rodent transplant models challenging. Recent insights into NK function and NK‐mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro‐environment. In this review, we summarize NK cell populations in the peripheral blood and liver, and we explore the data regarding the expression and function of immune checkpoint molecules on NK cells. We also hypothesize about the roles they could play in liver transplantation and discuss how they might be harnessed therapeutically in transplant sciences.
Collapse
Affiliation(s)
- Jennifer Halma
- Pediatric Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Stephen Pierce
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Rebecca McLennan
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Todd Bradley
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA.,Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Ryan Fischer
- Pediatric Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA.,Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
| |
Collapse
|
|
28
|
Vogel A, Sterneck M, Vondran F, Waidmann O, Klein I, Lindig U, Nadalin S, Settmacher U, Tacke F, Schlitt HJ, Wege H. [The use of immuno-oncologic therapy in hepatocellular carcinoma in the context of liver transplantation. An interdisciplinary benefit/risk assessment]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 60:184-191. [PMID: 34670296 DOI: 10.1055/a-1649-8643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Multiple systemic therapy options have been recently approved for the treatment of hepatocellular carcinoma (HCC). In particular, immuno-oncology combination therapies can now achieve impressive response rates and significantly prolonged survival with good tolerability. These immuno-oncology (IO)-based combinations are currently not only evaluated for the therapy of advanced HCC, but increasingly also in earlier stages in terms of peri-interventional therapy concepts and also for down-sizing to local therapies. In the context of liver transplantation (LTx), a particularly critical benefit/risk assessment must be made before the use of immunotherapeutics in the context of multimodal concepts, since the risk of a potentially lethal rejection can be significantly increased by immunotherapy. METHODS This review is based on a selective literature search performed between December 2020 and April 2021 in the PubMed and Cochrane Library databases. Guidelines, expert opinions, and recommendations from professional societies were given special consideration. RESULTS Nearly one in five LTx in Germany are performed due to HCCs. In this context, LTx is a curative therapy option not only for the underlying liver disease but also for the malignant tumor. Individual case reports indicate that IO therapy prior to LTx may increase the risk of rejection or liver failure after subsequent liver transplantation. Since 2015, immunotherapeutics have also been widely used for tumor therapy in patients after LTx. In small case series, rejection rates of 36%, associated with rejection-related mortality of 20% of treated patients, have been described. A similar incidence of rejection has also been described following the use of immunotherapeutics in patients after other organ transplantations. CONCLUSION In the context of organ transplantation, IO therapy carries the risk of graft rejection, which can lead to graft loss and also patient death. However, from today's point of view, IO-based therapy can be considered in the context of organ transplantation with a careful benefit/risk assessment.
Collapse
Affiliation(s)
- Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Martina Sterneck
- I. Medizinische Klinik und Poliklinik, UKE Hamburg, Hamburg, Deutschland
| | - Florian Vondran
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Oliver Waidmann
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Ingo Klein
- Klinik und Poliklinik für Allgemein-, Viszeral-, Transplantations-, Gefäß- und Kinderchirurgie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Udo Lindig
- Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Deutschland
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Hans Jürgen Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Henning Wege
- I. Medizinische Klinik und Poliklinik, UKE Hamburg, Hamburg, Deutschland.,Cancer Center Esslingen, Klinikum Esslingen, Esslingen, Deutschland
| |
Collapse
|
|
29
|
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.
Collapse
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
| |
Collapse
|
|
30
|
Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
Collapse
Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| |
Collapse
|
|
31
|
Qiao ZY, Zhang ZJ, Lv ZC, Tong H, Xi ZF, Wu HX, Chen XS, Xia L, Feng H, Zhang JJ, Xia Q. Neoadjuvant Programmed Cell Death 1 (PD-1) Inhibitor Treatment in Patients With Hepatocellular Carcinoma Before Liver Transplant: A Cohort Study and Literature Review. Front Immunol 2021; 12:653437. [PMID: 34349755 PMCID: PMC8326904 DOI: 10.3389/fimmu.2021.653437] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.
Collapse
Affiliation(s)
- Zi-Yun Qiao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Jie Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Cheng Lv
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huan Tong
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Shanghai, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao-Xiang Wu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Song Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China.,Shanghai Institute of Transplantation, Shanghai, China
| | - Jian-Jun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China.,Shanghai Institute of Transplantation, Shanghai, China
| |
Collapse
|
|
32
|
Mastoridis S, Londoño MC, Kurt A, Kodela E, Crespo E, Mason J, Bestard O, Martínez-Llordella M, Sánchez-Fueyo A. Impact of donor extracellular vesicle release on recipient cell "cross-dressing" following clinical liver and kidney transplantation. Am J Transplant 2021; 21:2387-2398. [PMID: 32515541 DOI: 10.1111/ajt.16123] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 05/26/2020] [Accepted: 05/30/2020] [Indexed: 01/25/2023]
Abstract
In several murine models of transplantation, the "cross-dressing" of recipient antigen presenting cells (APCs) with intact donor major histocompatibility complex (MHC) derived from allograft-released small extracellular vesicles (sEVs) has been recently described as a key mechanism in eliciting and sustaining alloimmune responses. Investigation of these processes in clinical organ transplantation has, however, been hampered by the lack of sensitivity of conventional instruments and assays. We have employed advanced imaging flow cytometry (iFCM) to explore the kinetics of allograft sEV release and the extent to which donor sEVs might induce cross-dressing following liver and kidney transplantation. We report for the first time that recipient APC cross-dressing can be transiently detected in the circulation shortly after liver, but not kidney, transplantation in association with the release of HLA-bearing allograft-derived sEVs. In liver transplant recipients the majority of circulating cells exhibiting donor HLA are indeed cross-dressed cells and not passenger leukocytes. In keeping with experimental animal data, the downstream functional consequences of the transfer of circulating sEVs harvested from human transplant recipients varies depending on the type of transplant and time posttransplant. sEVs released shortly after liver, but not kidney, transplantation exhibit immunoinhibitory effects that could influence liver allograft immunogenicity.
Collapse
Affiliation(s)
- Sotiris Mastoridis
- Medical Research Council (MRC) Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom
| | - María-Carlota Londoño
- Medical Research Council (MRC) Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom.,Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
| | - Ada Kurt
- Medical Research Council (MRC) Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom
| | - Elisavet Kodela
- Medical Research Council (MRC) Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom
| | - Elena Crespo
- Kidney Transplant Unit, Bellvitge University Hospital, Barcelona, Spain
| | - John Mason
- Department of Physiology, Anatomy & Genetics, University of Oxford, United Kingdom
| | - Oriol Bestard
- Kidney Transplant Unit, Bellvitge University Hospital, Barcelona, Spain
| | - Marc Martínez-Llordella
- Medical Research Council (MRC) Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom
| | - Alberto Sánchez-Fueyo
- Medical Research Council (MRC) Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom
| |
Collapse
|
|
33
|
Florou V, Puri S, Garrido-Laguna I, Wilky BA. Considerations for immunotherapy in patients with cancer and comorbid immune dysfunction. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1035. [PMID: 34277835 PMCID: PMC8267318 DOI: 10.21037/atm-20-5207] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors have been widely incorporated for cancer treatment in a variety of solid and hematologic malignancies. Multiple clinical trials have demonstrated the efficacy of PD-1/PD-L1 and CTLA-4 axis inhibition in the metastatic and adjuvant settings. Due to the risks of autoimmune toxicity with these agents, stringent inclusion/exclusion criteria were employed in those initial clinical trials. These criteria led to exclusion or underrepresentation of a variety of patient populations with underlying immune dysfunction. These populations included patients with preexisting autoimmune diseases, solid organ or bone marrow transplant recipients, patients with HIV or viral hepatitis infections, patients receiving concurrent chronic steroid therapy, as well as patients who were elderly, pregnant, or had poor performance status. Thus, established guidelines on the use of immune checkpoint inhibitors in these patients are lacking, and evidence to support efficacy or toxicity are overall limited to retrospective studies and case series. Fortunately, ongoing clinical trials are now including these patients and are shedding light on whether these underrepresented populations can also safely benefit from immune checkpoint inhibitor therapies. In this review, we summarize the most clinically relevant available data on the use of checkpoint inhibitors in immunocompromised patient groups with a primary focus on safety.
Collapse
Affiliation(s)
- Vaia Florou
- Department of Internal Medicine, Division of Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Sonam Puri
- Department of Internal Medicine, Division of Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Ignacio Garrido-Laguna
- Department of Internal Medicine, Division of Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Breelyn A Wilky
- Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| |
Collapse
|
|
34
|
Minari R, Bonatti F, Mazzaschi G, Dodi A, Facchinetti F, Gelsomino F, Cinquegrani G, Squadrilli A, Bordi P, Buti S, Bersanelli M, Leonetti A, Cosenza A, Ferri L, Rapacchi E, Quaini F, Ardizzoni A, Tiseo M. PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors. TUMORI JOURNAL 2021; 108:47-55. [PMID: 34002648 DOI: 10.1177/03008916211014954] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To investigate the role of CTLA-4, PD-1 (programmed death-1), and PD-L1 (programmed death-ligand 1) single nucleotide polymorphisms (SNPs) in predicting clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). METHODS A total of 166 consecutive patients were included. We correlated SNPs with clinical benefit, progression-free survival, time to treatment failure, and overall survival and evaluated the incidence of SNPs in nonresponder and long clinical benefit groups. RESULTS Considering the entire cohort, no correlation was found between SNPs and clinical outcome; however, PD-L1 rs4143815 SNP and the long clinical benefit group showed a statistically significant association (p = 0.02). The nonresponder cohort displayed distinctive PD-L1 haplotype (p = 0.05). CONCLUSION PD-L1 SNPs seem to be marginally involved in predicting clinical outcome of NSCLC treated with ICI, but further investigations are required.
Collapse
Affiliation(s)
- Roberta Minari
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Giulia Mazzaschi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine & Surgery, University of Parma
| | | | - Francesco Facchinetti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy.,Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France
| | | | | | - Anna Squadrilli
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Paola Bordi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Agnese Cosenza
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Leonarda Ferri
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Elena Rapacchi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Andrea Ardizzoni
- Medical Oncology, AOU Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Marcello Tiseo
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine & Surgery, University of Parma
| |
Collapse
|
|
35
|
Lucander ACK, Nguyen H, Foote JB, Cooper DKC, Hara H. Immunological selection and monitoring of patients undergoing pig kidney transplantation. Xenotransplantation 2021; 28:e12686. [PMID: 33880816 DOI: 10.1111/xen.12686] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/03/2021] [Accepted: 03/18/2021] [Indexed: 01/04/2023]
Abstract
Pig kidney xenotransplantation has the potential to alleviate the current shortage of deceased and living human organs and provide patients with end-stage renal disease with a greater opportunity for long-term survival and a better quality of life. In recent decades, advances in the genetic engineering of pigs and in immunosuppressive therapy have permitted the resolution of many historical obstacles to the success of pig kidney transplantation in nonhuman primates. Pig kidney xenotransplantation may soon be translated to the clinic. Given the potential risks of kidney xenotransplantation, particularly of immunologic rejection of the graft, potential patients must be carefully screened for inclusion in the initial clinical trials and immunologically monitored diligently post-transplantation. We provide an overview of the immunological methods we believe should be used to (i) screen potential patients for the first clinical trials to exclude those with a higher risk of rejection, and (ii) monitor patients with a pig kidney graft to determine their immunological response to the graft.
Collapse
Affiliation(s)
- Aaron C K Lucander
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Huy Nguyen
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| |
Collapse
|
|
36
|
Chen GH, Wang GB, Huang F, Qin R, Yu XJ, Wu RL, Hou LJ, Ye ZH, Zhang XH, Zhao HC. Pretransplant use of toripalimab for hepatocellular carcinoma resulting in fatal acute hepatic necrosis in the immediate postoperative period. Transpl Immunol 2021; 66:101386. [PMID: 33744409 DOI: 10.1016/j.trim.2021.101386] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/13/2021] [Accepted: 03/15/2021] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibitors are increasingly used in the treatment of various solid tumors, including hepatocellular carcinoma (HCC). For liver transplant recipients, the safety of using immune checkpoint inhibitors before or after transplantation remains to be further explored. Former reports were mainly about posttransplant use of immune checkpoint inhibitors resulting in allograft rejection. Here we present one HCC patient who received toripalimab (an immune checkpoint inhibitor currently in phase 3 clinical trial for HCC) therapy before undergoing liver transplantation. He finally suffered fatal acute hepatic necrosis which is likely to be related to the acute immune rejection caused by the pretransplant use of toripalimab.
Collapse
Affiliation(s)
- Guang-Hou Chen
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Guo-Bin Wang
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Fan Huang
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Rong Qin
- Department of Pathology, Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Xiao-Jun Yu
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Ruo-Lin Wu
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Liu-Jin Hou
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Zheng-Hui Ye
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Xing-Hua Zhang
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Hong-Chuan Zhao
- Organ Transplantation Center, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| |
Collapse
|
|
37
|
Shi GM, Wang J, Huang XW, Huang XY, He YF, Ji Y, Chen Y, Wu D, Lu JC, Sun QM, Liu WR, Wang T, Yang LX, Hou YY, Shi YH, Sun J, Xiao YS, Wang Z, Fan J, Bertagnolli MM, Zhou J. Graft Programmed Death Ligand 1 Expression as a Marker for Transplant Rejection Following Anti-Programmed Death 1 Immunotherapy for Recurrent Liver Tumors. Liver Transpl 2021; 27:444-449. [PMID: 32897657 DOI: 10.1002/lt.25887] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 07/12/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Guo-Ming Shi
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiping Wang
- Division of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Xiao-Wu Huang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Xiao-Yong Huang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yi-Feng He
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Chen
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China
| | - Dong Wu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Cheng Lu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China
| | - Qi-Man Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Wei-Ren Liu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ting Wang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liu-Xiao Yang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Yong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Hong Shi
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jian Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yong-Sheng Xiao
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Zheng Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Monica M Bertagnolli
- Division of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai, China.,Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| |
Collapse
|
|
38
|
Relationship of PD-1 (PDCD1) and PD-L1 (CD274) Single Nucleotide Polymorphisms with Polycystic Ovary Syndrome. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9596358. [PMID: 33521133 PMCID: PMC7817229 DOI: 10.1155/2021/9596358] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 11/30/2020] [Accepted: 12/18/2020] [Indexed: 12/13/2022]
Abstract
This study is to investigate the relationship of programmed cell death 1 (PD-1; also known as PDCD1) and programmed death-1-ligand 1 (PD-L1; also known as CD274) single nucleotide polymorphisms (SNPs) with polycystic ovary syndrome (PCOS). This study enrolled 330 PCOS patients and 350 matched controls. ELISA was used to detect the PD-1 and PD-L1 levels in serum. SnaPshot genotyping was performed to analyze the PD-1 and PD-L1 genotyping. Linkage disequilibrium and haplotype of TagSNP loci of PD-1 and PD-L1 genes were also detected. The relationship of genotypes and alleles with PCOS was analyzed. The levels of PD-1 and PD-L1 in the serum of PCOS patients were significantly lower than those in the control group (P < 0.01). The haplotype TT of PD-1 gene at rs10204525 and rs7421861 loci was significantly lower in the PCOS group than in the control group (P < 0.001, OR = 0.67, and 95%CI = 0.54‐0.84). PD-L1 gene SNP loci rs2282055, rs2890658, rs10125854, and rs702275 had linkage disequilibrium. The haplotypes TAAA, GAAC, GAGC, GCAA, and TCGA of PD-L1 gene SNP loci were significantly higher in PCOS patients than in the control group, whereas haplotypes GAAA, TAAC, TCAA, GCGA, GCAC, and TCGC of PD-L1 gene SNP loci were significantly lower in PCOS patients than in the control group. PD-1 and PD-L1 SNPs may be related to the pathogenesis of PCOS. PD-1 gene SNP loci rs10204525 and rs7421861 and PD-L1 gene SNP loci rs2282055, rs2890658, rs10125854, and rs702275 may be new candidate polymorphic loci for PCOS.
Collapse
|
|
39
|
Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 2021; 70:204-214. [PMID: 32747413 PMCID: PMC7788203 DOI: 10.1136/gutjnl-2020-321702] [Citation(s) in RCA: 169] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/27/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023]
Abstract
Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.
Collapse
Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria .,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Worthersee, Klagenfurt, Kärnten, Austria
| |
Collapse
|
|
40
|
Niu D, Ma X, Yuan T, Niu Y, Xu Y, Sun Z, Ping Y, Li W, Zhang J, Wang T, Church GM. Porcine genome engineering for xenotransplantation. Adv Drug Deliv Rev 2021; 168:229-245. [PMID: 32275950 DOI: 10.1016/j.addr.2020.04.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 03/28/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023]
Abstract
The extreme shortage of human donor organs for treatment of patients with end-stage organ failures is well known. Xenotransplantation, which might provide unlimited organ supply, is a most promising strategy to solve this problem. Domestic pigs are regarded as ideal organ-source animals owing to similarity in anatomy, physiology and organ size to humans as well as high reproductive capacity and low maintenance cost. However, several barriers, which include immune rejection, inflammation and coagulative dysfunctions, as well as the cross-species transmission risk of porcine endogenous retrovirus, blocked the pig-to-human xenotransplantation. With the rapid development of genome engineering technologies and the potent immunosuppressive medications in recent years, these barriers could be eliminated through genetic modification of pig genome together with the administration of effective immunosuppressants. A number of candidate genes involved in the regulation of immune response, inflammation and coagulation have been explored to optimize porcine xenograft survival in non-human primate recipients. PERV inactivation in pigs has also been accomplished to firmly address the safety issue in pig-to-human xenotransplantation. Many encouraging preclinical milestones have been achieved with some organs surviving for years. Therefore, the clinical trials of some promising organs, such as islet, kidney and heart, are aimed to be launched in the near future.
Collapse
Affiliation(s)
- Dong Niu
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, P.R. China
| | - Xiang Ma
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, P.R. China
| | - Taoyan Yuan
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang 310021, China
| | - Yifan Niu
- Nanjing Kgene Genetic Engineering Co., Ltd, Nanjing, Jiangsu 211300, China
| | - Yibin Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zhongxin Sun
- Cosmetic & Plastic Surgery Department, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, China
| | - Yuan Ping
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Weifen Li
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Jufang Zhang
- Cosmetic & Plastic Surgery Department, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, China.
| | - Tao Wang
- Nanjing Kgene Genetic Engineering Co., Ltd, Nanjing, Jiangsu 211300, China.
| | - George M Church
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138, USA.
| |
Collapse
|
|
41
|
Delyon J, Zuber J, Dorent R, Poujol-Robert A, Peraldi MN, Anglicheau D, Lebbe C. Immune Checkpoint Inhibitors in Transplantation-A Case Series and Comprehensive Review of Current Knowledge. Transplantation 2021; 105:67-78. [PMID: 32355121 DOI: 10.1097/tp.0000000000003292] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Cancer is a leading cause of morbidity and deaths in solid organ transplant recipients. In immunocompetent patients, cancer prognosis has been dramatically improved with the development of immune checkpoint inhibitors (ICI), as programmed cell death protein 1/programmed death-ligand 1 and cytotoxic T lymphocyte-associated antigen 4 inhibitors, that increase antitumor immune responses. ICI has been developed outside of the scope of transplantation because of the theoretical risk of graft rejection, which has later been confirmed by the publication of several cases and small series. The use of ICI became unavoidable for treating advanced cancers including in organ transplant patients, but their management in this setting remains highly challenging, as to date no strategy to adapt the immunosuppression and to prevent graft rejection has been defined. In this article, we report a monocentric series of 5 solid organ transplant recipients treated with ICI and provide a comprehensive review of current knowledge of ICI management in the setting of solid organ transplantation. Strategies warranted to increase knowledge through collecting more exhaustive data are also discussed.
Collapse
Affiliation(s)
- Julie Delyon
- Department of Dermatology, AP-HP Hôpital Saint Louis, Université de Paris, INSERM U976, Team 1, HIPI, Paris, France
| | - Julien Zuber
- Department of Nephrology and Kidney Transplantation, University Hospital Center (CHU) Necker, Université de Paris, Paris, France
| | - Richard Dorent
- Department of Cardiac Surgery, AP-HP, Bichat-Claude Bernard University Hospital, Paris, France
| | - Armelle Poujol-Robert
- Department of Hepatology, AP-HP, Hôpital Saint-Antoine, UPMC University, Paris, France
| | - Marie-Noelle Peraldi
- Department of Nephrology, AP-HP Hôpital Saint Louis, Université de Paris, Paris, France
| | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, University Hospital Center (CHU) Necker, Université de Paris, Paris, France
| | - Celeste Lebbe
- Department of Dermatology, AP-HP Hôpital Saint Louis, Université de Paris, INSERM U976, Team 1, HIPI, Paris, France
| |
Collapse
|
|
42
|
Mastoridis S, Martinez-Llordella M, Sanchez-Fueyo A. Extracellular vesicles as mediators of alloimmunity and their therapeutic potential in liver transplantation. World J Transplant 2020; 10:330-344. [PMID: 33312894 PMCID: PMC7708876 DOI: 10.5500/wjt.v10.i11.330] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/06/2020] [Accepted: 11/17/2020] [Indexed: 02/05/2023] Open
Abstract
Extracellular vesicles (EVs) are a heterogenous group of nanosized, membrane-bound particles which are released by most cell types. They are known to play an essential role in cellular communication by way of their varied cargo which includes selectively enriched proteins, lipids, and nucleic acids. In the last two decades, wide-ranging evidence has established the involvement of EVs in the regulation of immunity, with EVs released by immune and non-immune cells shown to be capable of mediating immune stimulation or suppression and to drive inflammatory, autoimmune, and infectious disease pathology. More recently, studies have demonstrated the involvement of allograft-derived EVs in alloimmune responses following transplantation, with EVs shown to be capable of eliciting allograft rejection as well as promoting tolerance. These insights are necessitating the reassessment of standard paradigms of T cell alloimmunity. In this article, we explore the latest understanding of the impact of EVs on alloresponses following transplantation and we highlight the recent technological advances which have enabled the study of EVs in clinical transplantation. Furthermore, we discuss the rapid progress afoot in the development of EVs as novel therapeutic vehicles in clinical transplantation with particular focus on liver transplantation.
Collapse
Affiliation(s)
- Sotiris Mastoridis
- Department ofSurgery, Oxford University Hospitals, Oxford OX37LE, United Kingdom
| | - Marc Martinez-Llordella
- Institute of Liver Studies, King's College Hospital, Medical Research Council (MRC) Centre for Transplantation, London SE59NU, United Kingdom
| | - Alberto Sanchez-Fueyo
- Department of Liver Sciences, King's College Hospital, Medical Research Council (MRC) Centre for Transplantation, London SE59NU, United Kingdom
| |
Collapse
|
|
43
|
Lu J, Wu Z, Peng J, Xu S, Zhou L, Lin Y, Wang Y, Yin W, Lu J. Programmed death-ligand 1 single nucleotide polymorphism affects breast cancer chemosensitivity and adverse events in the neoadjuvant setting. Int J Biol Markers 2020; 35:90-101. [PMID: 33073683 DOI: 10.1177/1724600820926172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE We aimed to determine whether single nucleotide polymorphisms in the PD-L1 gene are related to the response and adverse events of patients receiving neoadjuvant therapy and to explore the mechanism. METHODS Nine single nucleotide polymorphisms of PD-L1 were selected and tested among patients before neoadjuvant therapy. Four models were used in single nucleotide polymorphism genotype analysis: the addictive model compared TT vs TA vs AA; the dominant model compared TT vs TA+AA; the recessive model compared TT+TA vs AA; and the over-dominant model compared TT+AA vs TA (A as the minor allele). We analyzed the associations between single nucleotide polymorphism genotypes and pathological complete response, disease-free survival, and adverse events. Overexpression of the targeted microRNA was carried out using microRNA mimics. Logistic regression was used to analyze the associations between different single nucleotide polymorphism genotypes and pathological complete response outcome. Kaplan-Meier plots and log-rank tests were used to compare disease-free survival between groups with different single nucleotide polymorphism genotypes. The Cox proportional hazards model was used to calculate the adjusted hazard ratio. The Spearman's correlation test was used to determine the correlations between different genotypes and adverse events. RESULTS rs4143815C>G was associated with better pathological complete response in the addictive and over-dominant models and with poorer disease-free survival in the recessive model. Patients with different genotypes had different adverse events. Overexpression of miR34c resulted in the downregulation of PD-L1 mRNA expression. CONCLUSION The PD-L1 single nucleotide polymorphism rs4143815 was associated with the pathological complete response rate, disease-free survival, and adverse events in breast cancer patients receiving neoadjuvant therapy. The interaction between miR34c and PD-L1 might be affected by rs4143815.
Collapse
Affiliation(s)
- Jinglu Lu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Ziping Wu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Shuguang Xu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Liheng Zhou
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Yanping Lin
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Yan Wang
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Wenjin Yin
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Jinsong Lu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| |
Collapse
|
|
44
|
d'Izarny-Gargas T, Durrbach A, Zaidan M. Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review. Am J Transplant 2020; 20:2457-2465. [PMID: 32027461 DOI: 10.1111/ajt.15811] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 01/21/2020] [Accepted: 01/26/2020] [Indexed: 02/06/2023]
Abstract
Solid organ transplant (SOT) is frequently complicated by cancers, which render immunosuppression challenging. Immune checkpoint inhibitors have emerged as treatments for many cancers. Data are lacking regarding efficacy and rejection risk in the SOT population. We conducted a systematic literature review and analyzed 83 cases of immune checkpoint inhibitor use for cancer in SOT. Two thirds of these patients received anti-programmed death ligand 1 therapy, 15.7% received anti-cytotoxic T lymphocyte-associated protein 4 therapy, and 10.8% received a combination. Allograft rejection occurred in 39.8% of patients, leading to end-stage organ failure in 71.0% of cases. Outcomes were similar across organs and immunotherapy regimens. The use of immunosuppressants other than steroids, time since transplant, and prior episodes of rejection were associated with the risk of rejection. The median overall survival of patients was 36 weeks. Most of the deaths were related to cancer progression. In nonkidney recipients, graft rejection was strongly associated with worse survival. At the end of the study, 19.3% of the patients were alive, free from rejection and tumor progression. This study highlights the difficult tradeoff facing oncologists and transplant specialists managing transplant recipients with cancer, and the need for prospective data and novel biomarkers for identifying the patients likely to benefit from immunotherapy in the SOT setting.
Collapse
Affiliation(s)
| | - Antoine Durrbach
- Department of Nephrology-Dialysis-Transplantation, Henri Mondor Hospital, APHP, Creteil, France.,Paris Saclay University, Le Kremlin-Bicêtre, France.,UMRS 1186, Villejuif, France
| | - Mohamad Zaidan
- Department of Nephrology-Dialysis-Trans, Bicêtre Hospital, APHP, Le Kremlin Bicêtre, France.,Paris Saclay University, Le Kremlin-Bicêtre, France
| |
Collapse
|
|
45
|
Fisher J, Zeitouni N, Fan W, Samie FH. Immune checkpoint inhibitor therapy in solid organ transplant recipients: A patient-centered systematic review. J Am Acad Dermatol 2020; 82:1490-1500. [DOI: 10.1016/j.jaad.2019.07.005] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/12/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023]
|
|
46
|
Escoin-Perez C, Blasco S, Juan-Vidal O. Immune checkpoint inhibitors in special populations. A focus on advanced lung cancer patients. Lung Cancer 2020; 144:1-9. [PMID: 32278215 DOI: 10.1016/j.lungcan.2020.03.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/25/2020] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Immune checkpoint inhibitors (ICIs), including those targeting programmed cell death 1 (PD-1), its ligand 1 (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have become the standard treatment for several malignancies, including lung cancer. However, some patient populations have been routinely excluded from clinical trials or are underrepresented in these studies, as is the case of elderly patients or patients with poor performance status, brain metastases, solid organ transplant, autoimmune diseases, chronic viral infections (such as human immunodeficiency virus or chronic viral hepatitis B and C), or organ dysfunction. Thus, the safety and efficacy of ICIs in these special populations is still unclear, despite regulatory approval of these agents. This review analyzes and summarizes the available information on the efficacy and safety of ICIs in these special populations, focusing on patients with lung cancer.
Collapse
Affiliation(s)
- Corina Escoin-Perez
- Department of Medical Oncology, Hospital Universitario de La Ribera, Crta. Corbera, Km1. 46600 Alzira, Valencia, Spain.
| | - Sara Blasco
- Department of Medical Oncology, Hospital de Sagunto, Av. Ramón y Cajal, s/n. 46520 Sagunto, Valencia, Spain.
| | - Oscar Juan-Vidal
- Department of Medical Oncology, Hospital Universitario y Politécnico La Fe, Av. Fernando Abril Martorell, 106. 46026, Valencia, Spain.
| |
Collapse
|
|
47
|
Nordness MF, Hamel S, Godfrey CM, Shi C, Johnson DB, Goff LW, O'Dell H, Perri RE, Alexopoulos SP. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant 2020; 20:879-883. [PMID: 31550417 PMCID: PMC10176099 DOI: 10.1111/ajt.15617] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/23/2019] [Accepted: 09/03/2019] [Indexed: 01/25/2023]
Abstract
Nivolumab is an immune checkpoint inhibitor (ICI) currently in phase 3 clinical trials for hepatocellular carcinoma. The safety of ICIs in recipients of organ allotransplant is unclear, and several reports of fatal alloimmune injury after posttransplant ICI use have been published. We present the first published case of nivolumab used in the pretransplant setting for HCC resulting in fatal acute hepatic necrosis in the immediate postoperative period from a profound immune reaction likely propagated by nivolumab. Further investigation and significant caution are needed in the evaluation of patients awaiting transplant who are receiving ICI therapy.
Collapse
Affiliation(s)
- Mina F Nordness
- Section of Surgical Sciences, Department of Surgery, Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Stephanie Hamel
- Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Caroline M Godfrey
- Section of Surgical Sciences, Department of Surgery, Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Chanjuan Shi
- Department of Pathology, Vanderbilt University Medical Center, Microbiology, Microbiology, Nashville, Tennessee
| | - Douglas B Johnson
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Laura W Goff
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Heather O'Dell
- Section of Surgical Sciences, Department of Surgery, Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Roman E Perri
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sophoclis P Alexopoulos
- Section of Surgical Sciences, Department of Surgery, Division of Hepatobiliary Surgery & Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee
| |
Collapse
|
|
48
|
Funazo TY, Nomizo T, Ozasa H, Tsuji T, Yasuda Y, Yoshida H, Sakamori Y, Nagai H, Hirai T, Kim YH. Clinical impact of low serum free T4 in patients with non-small cell lung cancer treated with nivolumab. Sci Rep 2019; 9:17085. [PMID: 31745135 PMCID: PMC6864095 DOI: 10.1038/s41598-019-53327-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022] Open
Abstract
Nivolumab improves the prognosis of non-small cell lung cancer (NSCLC) but can cause immune-related adverse events (irAEs). Reports have indicated longer progression-free survivals (PFSs) in patients with irAEs than in those without irAEs. We reported associations between programmed death ligand-1 (PD-L1) single nucleotide polymorphisms (SNPs) and PFS after nivolumab treatment. We hypothesized that adverse events might be associated with the SNPs of PD-L1. We analyzed data from 111 patients with NSCLC treated with nivolumab. The response rate was 14%, and the median PFS was 68 days. We found patients with the adverse event of low free tetraiodothyronine (fT4) had significantly longer PFSs than those without low fT4 (not reached vs 67 days; hazard ratio [HR], 0.297; P = 0.010). Moreover, median overall survival was longer in patients with low fT4 than those without low fT4 (not reached vs 556 days, HR, 0.139; P = 0.020). Patients with the T allele of rs1411262 (P = 0.0073) and with the A allele of rs822339 (P = 0.0204) developed low fT4. Patients with the T/T genotype had longer PFSs than with those with the C/T and C/C genotypes of rs1411262 (165 vs. 67 days, HR, 1.65; P = 0.040), and those with the A/A genotype had longer PFSs than those with the A/G and G/G genotypes of rs822339 (182 vs. 67 days, HR, 1.76; P = 0.025). In the patients with advanced NSCLC, low fT4 after nivolumab treatment was associated with significantly longer PFSs. The SNPs of PD-L1 may be associated with the adverse events of nivolumab.
Collapse
Affiliation(s)
- Tomoko Yamamoto Funazo
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Takashi Nomizo
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hiroaki Ozasa
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Takahiro Tsuji
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yuto Yasuda
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hironori Yoshida
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yuichi Sakamori
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hiroki Nagai
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Toyohiro Hirai
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Young Hak Kim
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| |
Collapse
|
|
49
|
Zhou G, Sprengers D, Mancham S, Erkens R, Boor PPC, van Beek AA, Doukas M, Noordam L, Campos Carrascosa L, de Ruiter V, van Leeuwen RWF, Polak WG, de Jonge J, Groot Koerkamp B, van Rosmalen B, van Gulik TM, Verheij J, IJzermans JNM, Bruno MJ, Kwekkeboom J. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules. J Hepatol 2019; 71:753-762. [PMID: 31195061 DOI: 10.1016/j.jhep.2019.05.026] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 05/29/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma is an aggressive hepatobiliary malignancy originating from biliary tract epithelium. Whether cholangiocarcinoma is responsive to immune checkpoint antibody therapy is unknown, and knowledge of its tumor immune microenvironment is limited. We aimed to characterize tumor-infiltrating lymphocytes (TILs) in cholangiocarcinoma and assess functional effects of targeting checkpoint molecules on TILs. METHODS We isolated TILs from resected tumors of patients with cholangiocarcinoma and investigated their compositions compared with their counterparts in tumor-free liver (TFL) tissues and blood, by flow cytometry and immunohistochemistry. We measured expression of immune co-stimulatory and co-inhibitory molecules on TILs, and determined whether targeting these molecules improved ex vivo functions of TILs. RESULTS Proportions of cytotoxic T cells and natural killer cells were decreased, whereas regulatory T cells were increased in tumors compared with TFL. While regulatory T cells accumulated in tumors, the majority of cytotoxic and helper T cells were sequestered at tumor margins, and natural killer cells were excluded from the tumors. The co-stimulatory receptor GITR and co-inhibitory receptors PD1 and CTLA4 were over-expressed on tumor-infiltrating T cells compared with T cells in TFL and blood. Antagonistic targeting of PD1 or CTLA4 or agonistic targeting of GITR enhanced effector molecule production and T cell proliferation in ex vivo stimulation of TILs derived from cholangiocarcinoma. The inter-individual variations in TIL responses to checkpoint treatments were correlated with differences in TIL immune phenotype. CONCLUSIONS Decreased numbers of cytotoxic immune cells and increased numbers of suppressor T cells that over-express co-inhibitory receptors suggest that the tumor microenvironment in cholangiocarcinoma is immunosuppressive. Targeting GITR, PD1 or CTLA4 enhances effector functions of tumor-infiltrating T cells, indicating that these molecules are potential immunotherapeutic targets for patients with cholangiocarcinoma. LAY SUMMARY The defense functions of immune cells are suppressed in cholangiocarcinoma tumors. Stimulating or blocking "immune checkpoint" molecules expressed on tumor-infiltrating T cells can enhance the defense functions of these cells. Therefore, these molecules may be promising targets for therapeutic stimulation of immune cells to eradicate the tumors and prevent cancer recurrence in patients with cholangiocarcinoma.
Collapse
Affiliation(s)
- Guoying Zhou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Shanta Mancham
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Remco Erkens
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Patrick P C Boor
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Adriaan A van Beek
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Lisanne Noordam
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Lucia Campos Carrascosa
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Valeska de Ruiter
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Roelof W F van Leeuwen
- Department of Hospital Pharmacy and Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Wojciech G Polak
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Belle van Rosmalen
- Department of Surgery, Academic Medical Center, Amsterdam, the Netherlands
| | - Thomas M van Gulik
- Department of Surgery, Academic Medical Center, Amsterdam, the Netherlands
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
| |
Collapse
|
|
50
|
Ho CM, Chen HL, Hu RH, Lee PH. Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: a review from a transplant oncology perspective. Ther Adv Med Oncol 2019; 11:1758835919843463. [PMID: 31065295 PMCID: PMC6487770 DOI: 10.1177/1758835919843463] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/18/2019] [Indexed: 12/14/2022] Open
Abstract
Without stringent criteria, liver transplantation for hepatocellular carcinoma (HCC) can lead to high cancer recurrence and poor prognosis in the current treatment context. Checkpoint inhibitors can lead to long survival by targeting coinhibitory pathways and promoting T-cell activity; thus, they have great potential for cancer immunotherapy. Therapeutic modulation of cosignaling pathways may shift paradigms from surgical prevention of recurrence to oncological intervention. Herein, we review the available evidence from a therapeutic perspective and focus on immune microenvironment perturbation by immunosuppressants and checkpoint inhibitors. Partial and reversible interleukin-2 signaling blockade is the mainstream strategy of immunosuppression for graft protection. Programmed cell death protein 1 (PD-1) is abundantly expressed on human liver allograft-infiltrating T-cells, which proliferate considerably after programmed death-ligand 1 (PD-L1) blockade. Clinically, checkpoint inhibitors are used in heart, liver, and kidney recipients with various cancers. Rejection can occur after checkpoint inhibitor administration through acute T-cell-mediated, antibody-mediated, or chronic allograft rejection mechanisms. Nevertheless, liver recipients may demonstrate favorable responses to treatment for HCC recurrence without rejection. Pharmacodynamically, substantial degrees of receptor occupancy can be achieved with lower doses, with favorable clinical outcomes. Manipulation of the immune microenvironment is a therapeutic niche that balances seemingly conflicting anticancer and graft protection needs. Additional translational and clinical studies emphasizing the comparative effectiveness of signaling networks within the immune microenvironment and conducting overall assessment of the immune microenvironment may aid in creating a therapeutic window and benefiting future liver recipients with HCC recurrence.
Collapse
Affiliation(s)
- Cheng-Maw Ho
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan South Road, Taipei 100, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Rey-Heng Hu
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|