Abstract Prostate cancer (PCa) remains a significant health burden as the most diagnosed malignancy and the second leading cause of cancer death in U. S. men. Androgen receptor (AR) signaling drives PCa progression, yet the effects of androgen deprivation therapy are short-lived, and castration-resistant prostate cancer (CRPC) inevitably emerges. CBP/p300, transcriptional co-activators, play crucial roles in regulating AR, MYC, and other oncogenic drivers. Our preliminary data and ongoing clinical trial findings suggest that CBP/p300 inhibition compromises AR/MYC activity, reducing PCa cell growth in vitro and in vivo. In addition to their contributions to PCa progression, AR and MYC can also modulate immune regulatory factors; however, the role of CBP/p300 in modulating T cell-regulatory pathways and immune evasion mechanisms in PCa remains poorly defined. The purpose of this study is to evaluate how CBP/p300 activity in tumor cells modulates immune signaling and surface expression of T cell regulatory factors, with the goal of defining mechanisms of immune suppression driven by AR/MYC and CBP/p300 interplay. Ultimately, these findings may lead to better treatments that address immune dysregulation in the TME and inform therapeutic strategies integrating CBP/p300 inhibition with immunotherapy. We performed transcriptomic profiling of multiple PCa cell lines following CBP or p300 knockdown or cells treated with pharmacological inhibition using the clinical CBP/p300 bromodomain inhibitor CCS1477. Differential pathway enrichment was used to identify key immune regulatory signatures downstream of CBP/p300. To assess functional outcomes, human and murine PCa cell lines were evaluated by flow cytometry for expression of immune-modulatory ligands involved in antigen presentation and T cell suppression. These studies parallel ongoing co-culture experiments with CD8+ T cells to determine whether CBP/p300 manipulation alters T cell function. Transcriptomic analyses revealed impacts on IL-2/STAT signaling, TNFα signaling via NF-κB, and Interferon response genes following CBP/p300 suppression. These data suggest CBP/p300 broadly regulate inflammatory signaling programs that intersect with AR/MYC activity, and this prompted subsequent flow cytometry analyses of surface expression of T cell–relevant ligands, including markers associated with antigen presentation and immune suppression. Our findings support a model in which CBP/p300 act as central transcriptional nodes linking AR/MYC signaling with immune dysregulation in PCa. These findings provide evidence that inhibition of CBP/p300 can be used to improve PCa patient outcomes, by both reducing PCa growth and enhancing immune function in the TME. Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions, or policies opinions of the USUHS, HJF, the DoW or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U. S. Government. Citation Format: Paula O. Cooper, Stefan DiFazio, Laila Scroggins, Raunak Shrestha, Leigh Ellis, Cara C. Schafer, Ayesha A. Shafi. Interplay of AR co-activators, CBP/p300, and immune regulation in prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr A011.
Cooper et al. (2026) studied this question.