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Blood. 2015 Jul 9;126(2):203-11. doi: 10.1182/blood-2015-01-622936. Epub 2015 Mar 23.

PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia.

Author information

1
Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; and Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
2
Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
3
Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; and.

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.

PMID:
25800048
PMCID:
PMC4497961
DOI:
10.1182/blood-2015-01-622936
[Indexed for MEDLINE]
Free PMC Article

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