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

Abstract

Key Points• In vivo PD-L1 blockade prevents CLL development in the Em-TCL1 adoptive transfer model. • In vivo PD-L1 blockade normalizes T-cell and myeloid cell populations and immune effector functions.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 Em-TCL1 mouse model for CLL. In this study, we treated mice after adoptive transfer of Em-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. (Blood. 2015;126(2):203-211)

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…61,63 Preclinical data on anti-PD-1 effects in CLL demonstrated restored CD8 T-cell cytotoxicity, immune synapse formation and prevention of CLL development in TCL-1 mouse models. 64,65 These observations and other preclinical data suggesting the importance of additional immune checkpoint pathways 66 provide a strong rationale for investigating immunomodulating therapies in CLL.…”

Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

“…These data indicate that PD-1 ligation delivers an inhibitory signal to CAR-mediated T-cell activation. Of interest, PD-L1 checkpoint blockade has been shown to normalize the T-cell compartment in the Em-TCL1 mouse model of CLL 30 ; however, even though PD-1 expression in CAR T cells in vivo has been observed, 8 its physiologic effects on the T-cell . Horizontal bars, boxes, and whiskers depict median, 25%/75% quartiles, and range, respectively.…”

BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

“…The Em-TCL1 model was selected because of its extensive prior characterization, including studies that demonstrated its utility in investigating tumor-induced immune defects. [50][51][52] Our results demonstrate that BRAF V600E accelerates Em-TCL1 B-cell leukemia development, likely because of a combination of decreased spontaneous apoptosis and enhanced immune suppression rather than increased proliferation. In addition, BRAF VE leukemia cells produced greater T-cell effects than Figure 6.…”