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.
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Authors
Volk, ValeryTheobald, Sebastian J
Danisch, Simon
Khailaie, Sahamoddin
Kalbarczyk, Maja
Schneider, Andreas
Bialek-Waldmann, Julia
Krönke, Nicole
Deng, Yun
Eiz-Vesper, Britta
Dragon, Anna Christina
von Kaisenberg, Constantin
Lienenklaus, Stefan
Bleich, Andre
Keck, James
Meyer-Hermann, Michael
Klawonn, Frank
Hammerschmidt, Wolfgang
Delecluse, Henri-Jacques
Münz, Christian
Feuerhake, Friedrich
Stripecke, Renata
Issue Date
2021-01-12
Metadata
Show full item recordAbstract
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.Citation
Front Oncol. 2021 Jan 12;10:614876. doi: 10.3389/fonc.2020.614876.Affiliation
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
FrontiersJournal
Frontiers in oncologyPubMed ID
33511078Type
ArticleLanguage
enISSN
2234-943Xae974a485f413a2113503eed53cd6c53
10.3389/fonc.2020.614876
Scopus Count
The following license files are associated with this item:
- Creative Commons
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