title: PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia.
abstract: Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint augments antitumor immunity and induces durable responses in patients with solid cancers, but data on clinical efficacy in leukemias are sparse. Chronic lymphocytic leukemia (CLL) is associated with a tumor-supportive microenvironment and a dysfunctional immune system, as shown by "exhausted" T cells, defective immunologic synapse formation, and immunosuppressive myeloid cells. These defects involve aberrant expression of PD-L1 and are closely mirrored in the Eµ-TCL1 mouse model for CLL. In this study, we treated mice after adoptive transfer of Eµ-TCL1 CLL with PD-L1-blocking antibodies, which prevented CLL development and was accompanied by a reactivation of immune effector functions. This included restoration of mature macrophages and major histocompatibility complex class II-expressing dendritic cells and prevention of aberrant and exhaustion-like T-cell phenotypes. In addition, PD-L1 blockade restored CD8 T-cell cytotoxicity and immune synapse formation and normalized T-cell cytokines and proliferation ex vivo and in vivo. Our data demonstrate that early PD-L1 blockade effectively corrects leukemia-induced immune dysfunction and thus prevents CLL development in mice. Targeting PD-L1/PD-1 interactions should therefore be further explored in clinical studies with CLL patients, ideally in combination with novel compounds to help eliminate CLL.
authors: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; and Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors: Fabienne
authors: F
authors: McClanahan
authors: Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors: Bola
authors: B
authors: Hanna
authors: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; and.
authors: Shaun
authors: S
authors: Miller
authors: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; and.
authors: Andrew James
authors: AJ
authors: Clear
authors: Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors: Peter
authors: P
authors: Lichter
authors: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; and.
authors: John G
authors: JG
authors: Gribben
authors: Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors: Martina
authors: M
authors: Seiffert
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007154:Immune System Diseases / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse