BET Inhibition Reforms the Immune Microenvironment and Alleviates T Cell Dysfunction in Chronic Lymphocytic Leukemia

Authors

Audrey L. Smith, University of Nebraska Medical CenterFollow
Sydney A. Skupa, University of Nebraska Medical CenterFollow
Alexandria P. Eiken, University of Nebraska Medical CenterFollow
Timothy E. Reznicek, University of Nebraska Medical CenterFollow
Elizabeth Schmitz, University of Nebraska Medical CenterFollow
Nolan Williams, University of Nebraska Medical Center
Dalia Y. Moore, University of Nebraska Medical CenterFollow
Christopher R. D'Angelo, University of Nebraska Medical CenterFollow
Avyakta Kallam, University of Nebraska Medical Center
Matthew A. Lunning, University of Nebraska Medical CenterFollow
Gregory Bociek, University of Nebraska Medical CenterFollow
Julie M. Vose, University of Nebraska Medical CenterFollow
Eslam Mohamed, California Northstate University
Anna R. Mahr, University of Nebraska at Omaha
Paul W. Denton, University of Nebraska at Omaha
Ben Powell, Plexxikon Inc.
Gideon Bollag, Opna Bio LLC
M. Jordan Rowley, University of Nebraska Medical CenterFollow
Dalia El-Gamal, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

JCI Insight

Publication Date

2024

Volume

9

Abstract

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.

MeSH Headings

Leukemia, Lymphocytic, Chronic, B-Cell, Tumor Microenvironment, Humans, Animals, Mice, T-Lymphocytes, Transcription Factors, Hepatocyte Nuclear Factor 1-alpha, Cell Proliferation, Bromodomain Containing Proteins, Proteins

DOI Link

10.1172/jci.insight.177054

ISSN

2379-3708

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Smith, Audrey L.; Skupa, Sydney A.; Eiken, Alexandria P.; Reznicek, Timothy E.; Schmitz, Elizabeth; Williams, Nolan; Moore, Dalia Y.; D'Angelo, Christopher R.; Kallam, Avyakta; Lunning, Matthew A.; Bociek, Gregory; Vose, Julie M.; Mohamed, Eslam; Mahr, Anna R.; Denton, Paul W.; Powell, Ben; Bollag, Gideon; Rowley, M. Jordan; and El-Gamal, Dalia, "BET Inhibition Reforms the Immune Microenvironment and Alleviates T Cell Dysfunction in Chronic Lymphocytic Leukemia" (2024). Journal Articles: Oncology and Hematology. 14.
https://digitalcommons.unmc.edu/com_onchem_articles/14