دورية أكاديمية
BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia.
| العنوان: | BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia. |
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| المؤلفون: | 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. |
| المصدر: | JCI insight [JCI Insight] 2024 May 22; Vol. 9 (10). Date of Electronic Publication: 2024 May 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Leukemia, Lymphocytic, Chronic, B-Cell*/immunology , Leukemia, Lymphocytic, Chronic, B-Cell*/drug therapy , Tumor Microenvironment*/immunology , Tumor Microenvironment*/drug effects , T-Lymphocytes*/immunology , T-Lymphocytes*/drug effects , T-Lymphocytes*/metabolism, Humans ; Animals ; Mice ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Hepatocyte Nuclear Factor 1-alpha/metabolism ; Hepatocyte Nuclear Factor 1-alpha/genetics ; Cell Proliferation/drug effects ; Bromodomain Containing Proteins ; Proteins |
| مستخلص: | 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. |
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| معلومات مُعتمدة: | P20 GM103427 United States GM NIGMS NIH HHS; R35 GM147467 United States GM NIGMS NIH HHS; P30 CA036727 United States CA NCI NIH HHS; R00 CA208017 United States CA NCI NIH HHS; K99 CA208017 United States CA NCI NIH HHS; T32 CA009476 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Drug therapy; Immunology; Leukemias; Oncology; T cells |
| المشرفين على المادة: | 0 (bromodomain and extra-terminal domain protein, human) |
| تواريخ الأحداث: | Date Created: 20240522 Date Completed: 20240522 Latest Revision: 20240603 |
| رمز التحديث: | 20240603 |
| مُعرف محوري في PubMed: | PMC11141939 |
| DOI: | 10.1172/jci.insight.177054 |
| PMID: | 38775157 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.177054 |