Usage Information
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.
Authors
Audrey L. Smith, Sydney A. Skupa, Alexandria P. Eiken, Timothy E. Reznicek, Elizabeth Schmitz, Nolan Williams, Dalia Y. Moore, Christopher R. D’Angelo, Avyakta Kallam, Matthew A. Lunning, R. Gregory Bociek, Julie M. Vose, Eslam Mohamed, Anna R. Mahr, Paul W. Denton, Ben Powell, Gideon Bollag, M. Jordan Rowley, Dalia El-Gamal
Usage data is cumulative from January 2025 through January 2026.
| Usage | JCI | PMC |
|---|---|---|
| Text version | 1,353 | 208 |
| 277 | 37 | |
| Figure | 460 | 9 |
| Supplemental data | 128 | 10 |
| Citation downloads | 116 | 0 |
| Totals | 2,334 | 264 |
| Total Views | 2,598 | |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.
