PD-L1 Checkpoint Blockade Prevents Immune Dysfunction and Leukemia Development in a Mouse Model of Chronic Lymphocytic Leukemia
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une immunothérapie anti PD-L1 prévient le développement d'une leucémie lymphocytaire chronique
Blockade of the PD-1/PD-L1 immune checkpoint augments anti-tumor immunity and induces durable responses in patients with solid cancers, but data on clinical efficacy in leukemias is largely missing. Chronic lymphocytic leukemia (CLL) is associated with a tumor-supportive microenvironment and a dysfunctional immune system, as shown by "exhausted" T cells, defective immunological synapse formation, and immunosuppressive myeloid cells. These defects involve aberrant expression of PD-L1 and are closely mirrored in the E
μ-TCL1 mouse model for CLL. In the current study, we treated mice after adoptive transfer of Eμ-TCL1 CLL with PD-L1 blocking antibodies, which prevented CLL development and was accompanied with a re-activation of immune effector functions. This included restoration of mature macrophages and MHC 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. In summary, our data demonstrate that early PD-L1 blockade effectively corrects leukemia-induced immune dysfunction and as a consequence, 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.