| Autor: |
Smith AL; Eppley Institute for Research in Cancer and Allied Diseases., Skupa SA; Eppley Institute for Research in Cancer and Allied Diseases., Eiken AP; Eppley Institute for Research in Cancer and Allied Diseases., Reznicek TE; Department of Genetics, Cell Biology and Anatomy., Schmitz E; Eppley Institute for Research in Cancer and Allied Diseases., Williams N; Eppley Institute for Research in Cancer and Allied Diseases., Moore DY; Eppley Institute for Research in Cancer and Allied Diseases., D'Angelo CR; Division of Hematology and Oncology, Department of Internal Medicine, and.; Fred & Pamela Buffett Cancer Center (FPBCC), University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA., Kallam A; Division of Hematology and Oncology, Department of Internal Medicine, and.; Fred & Pamela Buffett Cancer Center (FPBCC), University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA., Lunning MA; Division of Hematology and Oncology, Department of Internal Medicine, and.; Fred & Pamela Buffett Cancer Center (FPBCC), University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA., Bociek RG; Division of Hematology and Oncology, Department of Internal Medicine, and.; Fred & Pamela Buffett Cancer Center (FPBCC), University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA., Vose JM; Division of Hematology and Oncology, Department of Internal Medicine, and.; Fred & Pamela Buffett Cancer Center (FPBCC), University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA., Mohamed E; College of Medicine and College of Graduate Studies, California Northstate University, Elk Grove, California, USA., Mahr AR; Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, USA., Denton PW; Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, USA., Powell B; Plexxikon Inc., South San Francisco, California, USA., Bollag G; Opna Bio LLC, South San Francisco, California, USA., Rowley MJ; Department of Genetics, Cell Biology and Anatomy., El-Gamal D; Eppley Institute for Research in Cancer and Allied Diseases.; Fred & Pamela Buffett Cancer Center (FPBCC), University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA. |
| Abstrakt: |
Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (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 CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eμ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity. |
