PD-1/CTLA-4 Blockade Inhibits Epstein-Barr Virus-Induced Lymphoma Growth in a Cord Blood Humanized-Mouse Model

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. © 2016 ma et al.