title: PD-1/CTLA-4 Blockade Inhibits Epstein-Barr Virus-Induced Lymphoma Growth in a Cord Blood Humanized-Mouse Model.
abstract: Epstein-Barr virus (EBV) infection causes B cell lymphomas in humanized mouse models and contributes to a variety of different types of human lymphomas. T cells directed against viral antigens play a critical role in controlling EBV infection, and EBV-positive lymphomas are particularly common in immunocompromised hosts. We previously showed that EBV induces B cell lymphomas with high frequency in a cord blood-humanized mouse model in which EBV-infected human cord blood is injected intraperitoneally into NOD/LtSz-scid/IL2Rγnull (NSG) mice. Since our former studies showed that it is possible for T cells to control the tumors in another NSG mouse model engrafted with both human fetal CD34+ cells and human thymus and liver, here we investigated whether monoclonal antibodies that block the T cell inhibitory receptors, PD-1 and CTLA-4, enhance the ability of cord blood T cells to control the outgrowth of EBV-induced lymphomas in the cord-blood humanized mouse model. We demonstrate that EBV-infected lymphoma cells in this model express both the PD-L1 and PD-L2 inhibitory ligands for the PD-1 receptor, and that T cells express the PD-1 and CTLA-4 receptors. Furthermore, we show that the combination of CTLA-4 and PD-1 blockade strikingly reduces the size of lymphomas induced by a lytic EBV strain (M81) in this model, and that this anti-tumor effect requires T cells. PD-1/CTLA-4 blockade markedly increases EBV-specific T cell responses, and is associated with enhanced tumor infiltration by CD4+ and CD8+ T cells. In addition, PD-1/CTLA-4 blockade decreases the number of both latently, and lytically, EBV-infected B cells. These results indicate that PD-1/CTLA-4 blockade enhances the ability of cord blood T cells to control outgrowth of EBV-induced lymphomas, and suggest that PD-1/CTLA-4 blockade might be useful for treating certain EBV-induced diseases in humans.
authors.affiliation: Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Shi-Dong
authors.initials: SD
authors.lastname: Ma
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Xuequn
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Jones
authors.affiliation: German Cancer Research Centre (DKFZ) Unit F100, Heidelberg, Germany; Institut National de la Santé et de la Recherche Médicale Unit U1074, Heidelberg, Germany.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Zumwalde
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Akshat
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gumperz
authors.affiliation: Departments of Oncology and Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Kenney
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology; D005312:Fetal Blood; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*
chemical_list: D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor