PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations
Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to...
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2020.614876/full |
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| author | Valery Volk Valery Volk Valery Volk Sebastian J. Theobald Sebastian J. Theobald Simon Danisch Simon Danisch Sahamoddin Khailaie Maja Kalbarczyk Maja Kalbarczyk Andreas Schneider Julia Bialek-Waldmann Nicole Krönke Yun Deng Britta Eiz-Vesper Anna Christina Dragon Constantin von Kaisenberg Stefan Lienenklaus Andre Bleich James Keck Michael Meyer-Hermann Frank Klawonn Frank Klawonn Wolfgang Hammerschmidt Henri-Jacques Delecluse Christian Münz Friedrich Feuerhake Friedrich Feuerhake Renata Stripecke Renata Stripecke |
| author_facet | Valery Volk Valery Volk Valery Volk Sebastian J. Theobald Sebastian J. Theobald Simon Danisch Simon Danisch Sahamoddin Khailaie Maja Kalbarczyk Maja Kalbarczyk Andreas Schneider Julia Bialek-Waldmann Nicole Krönke Yun Deng Britta Eiz-Vesper Anna Christina Dragon Constantin von Kaisenberg Stefan Lienenklaus Andre Bleich James Keck Michael Meyer-Hermann Frank Klawonn Frank Klawonn Wolfgang Hammerschmidt Henri-Jacques Delecluse Christian Münz Friedrich Feuerhake Friedrich Feuerhake Renata Stripecke Renata Stripecke |
| author_sort | Valery Volk |
| collection | DOAJ |
| description | Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD. |
| first_indexed | 2024-12-16T10:02:13Z |
| format | Article |
| id | doaj.art-5b4cfb5359cb472f97b28bdc16bb898b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-16T10:02:13Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-5b4cfb5359cb472f97b28bdc16bb898b2022-12-21T22:35:46ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-01-011010.3389/fonc.2020.614876614876PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell DysregulationsValery Volk0Valery Volk1Valery Volk2Sebastian J. Theobald3Sebastian J. Theobald4Simon Danisch5Simon Danisch6Sahamoddin Khailaie7Maja Kalbarczyk8Maja Kalbarczyk9Andreas Schneider10Julia Bialek-Waldmann11Nicole Krönke12Yun Deng13Britta Eiz-Vesper14Anna Christina Dragon15Constantin von Kaisenberg16Stefan Lienenklaus17Andre Bleich18James Keck19Michael Meyer-Hermann20Frank Klawonn21Frank Klawonn22Wolfgang Hammerschmidt23Henri-Jacques Delecluse24Christian Münz25Friedrich Feuerhake26Friedrich Feuerhake27Renata Stripecke28Renata Stripecke29Laboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyGerman Centre for Infection Research (DZIF), Partner site Hannover, Hannover, GermanyInstitute for Pathology, Hannover Medical School, Hannover, GermanyLaboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyGerman Centre for Infection Research (DZIF), Partner site Hannover, Hannover, GermanyLaboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyGerman Centre for Infection Research (DZIF), Partner site Hannover, Hannover, GermanyDepartment of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyLaboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyGerman Centre for Infection Research (DZIF), Partner site Hannover, Hannover, GermanyLaboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyLaboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyInstitute for Pathology, Hannover Medical School, Hannover, GermanyViral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, SwitzerlandInstitute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, GermanyInstitute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, GermanyDepartment of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, GermanyInstitute for Laboratory Animal Science, Hannover Medical School, Hannover, GermanyInstitute for Laboratory Animal Science, Hannover Medical School, Hannover, GermanyThe Jackson Laboratory, Sacramento, CA, United StatesDepartment of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany0Biostatistics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany1Institute for Information Engineering, Ostfalia University, Wolfenbuettel, Germany2Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health and German Centre for Infection Research (DZIF), Partner site Munich, Munich, Germany3German Cancer Research Center (DKFZ), Institut National de la Santé et de la Recherche Médicale (INSERM) Unit U1074, Heidelberg, GermanyViral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, SwitzerlandInstitute for Pathology, Hannover Medical School, Hannover, Germany4Institute for Neuropathology, University Clinic Freiburg, Freiburg, GermanyLaboratory of Regenerative Immune Therapies Applied, REBIRTH - Research Center for Translational Regenerative Medicine, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyGerman Centre for Infection Research (DZIF), Partner site Hannover, Hannover, GermanyPost-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.https://www.frontiersin.org/articles/10.3389/fonc.2020.614876/fullhumanized miceimmuno-oncologyEpstein-Barr Virus (EBV)immune checkpoint inhibition (ICI)post-transplant lymphoproliferative disease (PTLD)lymphoma |
| spellingShingle | Valery Volk Valery Volk Valery Volk Sebastian J. Theobald Sebastian J. Theobald Simon Danisch Simon Danisch Sahamoddin Khailaie Maja Kalbarczyk Maja Kalbarczyk Andreas Schneider Julia Bialek-Waldmann Nicole Krönke Yun Deng Britta Eiz-Vesper Anna Christina Dragon Constantin von Kaisenberg Stefan Lienenklaus Andre Bleich James Keck Michael Meyer-Hermann Frank Klawonn Frank Klawonn Wolfgang Hammerschmidt Henri-Jacques Delecluse Christian Münz Friedrich Feuerhake Friedrich Feuerhake Renata Stripecke Renata Stripecke PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations Frontiers in Oncology humanized mice immuno-oncology Epstein-Barr Virus (EBV) immune checkpoint inhibition (ICI) post-transplant lymphoproliferative disease (PTLD) lymphoma |
| title | PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations |
| title_full | PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations |
| title_fullStr | PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations |
| title_full_unstemmed | PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations |
| title_short | PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations |
| title_sort | pd 1 blockade aggravates epstein barr virus post transplant lymphoproliferative disorder in humanized mice resulting in central nervous system involvement and cd4 t cell dysregulations |
| topic | humanized mice immuno-oncology Epstein-Barr Virus (EBV) immune checkpoint inhibition (ICI) post-transplant lymphoproliferative disease (PTLD) lymphoma |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2020.614876/full |
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