AUTHOR=Volk Valery , Theobald 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 

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

JOURNAL=Frontiers in Oncology

VOLUME=Volume 10 - 2020

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.614876

DOI=10.3389/fonc.2020.614876

ISSN=2234-943X

ABSTRACT=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, immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells are indicated. Immune checkpoint inhibition (ICI) has revolutionized the immunotherapy field, but the use of ICI to treat EBV+ PTLD was not established clinically. 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. 15-17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with the 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 two to five 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 PD-1, 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 and 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.