BET inhibition reforms the immune microenvironment and alleviates T-cell dysfunction in chronic lymphocytic leukemia

Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T-cell exhaustion greatly hinder functional anti-tumor T-cell responses in chronic lymphocytic leukemia (CLL). Bromodomain and extra-terminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T-cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent T-cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures, fostering improved T-cell proliferation and effector function in patient samples and murine models of CLL. These findings establish the immunomodulatory action of BET-i on CLL T-cells and support the use of BET inhibitors in treatment strategies for CLL. In order to assay the global effect of the BET inhibitor OPN-51107 on the chronic lymphocytic leukemia tumor microenvironment, Eμ-TCL1 adoptive transfer mice were treated with OPN-51107 or vehicle control for 3 weeks. Murine splenic cells and peripheral blood mononuclear cells (PBMCs) were then evaluated for gene expression changes using the NanoString PanCancer IO 360™ Panel.