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Therapeutic targeting of the p300/CBP bromodomain enhances the efficacy of immune checkpoint blockade therapy

Oncogene volume 44, pages 2386–2395 (2025)Cite this article

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Abstract

Blockade of immune checkpoints, such as programmed death-ligand 1 (PD-L1), has shown promise in cancer treatment; however, clinical response remains limited in many cancer types. Our previous research demonstrated that p300/CBP mediates the acetylation of the PD-L1 promoter, regulating PD-L1 expression. In this study, we further investigated the role of the p300/CBP bromodomain in regulating PD-L1 expression using CCS1477, a selective bromodomain inhibitor developed by our team. We found that the p300/CBP bromodomain is essential for H3K27 acetylation at PD-L1 enhancers. Inhibiting this modification significantly reduced enhancer activity and PD-L1 transcription, including exosomal PD-L1, which has been implicated as key contributors to resistance against PD-L1 blockade therapy in various cancers. Furthermore, CCS1477 treatment resulted in a marked reduction of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) by inhibiting key cytokines such as IL6, CSF1, and CSF2, which are crucial for MDSC differentiation and recruitment. By reducing PD-L1 expression and modulating the immunosuppressive TME, CCS1477 creates a more favorable environment for tumor-infiltrating lymphocytes, significantly enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Notably, these effects were observed in both prostate cancer and melanoma models, underscoring the broad therapeutic potential of p300/CBP bromodomain inhibition in improving ICB outcomes.

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Fig. 1: Targeting p300/CBP bromodomain decreases PCa PD-L1 expression in vitro.
Fig. 2: CCS1477 decreases PCa PD-L1 expression in vivo.
Fig. 3: CCS1477 enhances PD-L1 blockade therapy in PCa.
Fig. 4: CCS1477 enhances the efficacy of ICB therapy in melanoma.
Fig. 5: CCS1477 treatment reduces MDSCs population in tumor bearing mice.
Fig. 6: CCS1477 down-regulated IL6/JAK pathway.

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Data availability

All data supporting the findings of this study are either included in the manuscript or available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by NIH grants R01 CA256893 (XL), R01 CA264652 (XL), R01 CA157429 (XL), R01 CA272483 (XL). This research was supported by pilot funding (JL) provided by the Support from the University of Kentucky Markey Cancer Center’s Cancer Center Support Grant (P30 CA177558). The work was also supported by Biospecimen Procurement and Translational Pathology, Biostatistics and Bioinformatics, Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558).

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Author notes

  1. These authors contributed equally: Jinghui Liu, Xinyi Wang.

Authors and Affiliations

  1. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA

    Jinghui Liu, Xinyi Wang, Hamed Maasoumyhaghighi, Mansoureh Nouri, Meng Wu, Jia Peng, Xiongjian Rao, Ruixin Wang, Sai Wu, Jianlin Wang, Zhiguo Li & Xiaoqi Liu

  2. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA

    Jinghui Liu, Daheng He & Xiaoqi Liu

  3. CellCentric Ltd, Chesterford Research Park, Cambridge, CB10 1XL, UK

    Nigel Brooks, Neil Pegg & Kris Frese

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Contributions

XL designed and supervised the project. JL designed and performed the experiments, analyzed the data, and wrote the manuscript. XW conducted xenograft tumor harvesting and flow cytometry analysis. DH performed RNA-seq data analysis. HM and MN carried out the CRISPR knockout assays. MW and JP performed and evaluated immunofluorescence staining. XR, RW, SW, JW, and ZL contributed to manuscript editing. NB, NP, and KF developed and provided CCS1477.

Corresponding authors

Correspondence to Jinghui Liu or Xiaoqi Liu.

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Competing interests

NB, NP, and KF are employees and shareholders of CellCentric Ltd. Additionally, Neil Pegg serves as a board director and is listed as the inventor on patents related to CCS1477.

Ethics approval and consent to participate

All procedures involving animals were carried out in compliance with institutional guidelines and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Kentucky (Protocol No.: 2020-3685). No human subjects were involved in this study.

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Liu, J., Wang, X., He, D. et al. Therapeutic targeting of the p300/CBP bromodomain enhances the efficacy of immune checkpoint blockade therapy. Oncogene 44, 2386–2395 (2025). https://doi.org/10.1038/s41388-025-03417-w

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