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p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer

Oncogene volume 39, pages 3939–3951 (2020)Cite this article

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Abstract

Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer, including prostate cancer (PCa), is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers, including PCa. This suggests that cutting off the secretion or expression of PD-L1 might improve the response rate of PD-L1 blockade therapy in PCa treatment. Here we report that p300/CBP inhibition by a small molecule p300/CBP inhibitor dramatically enhanced the efficacy of PD-L1 blockade treatment in a syngeneic model of PCa by blocking both the intrinsic and IFN-γ-induced PD-L1 expression. Mechanistically, p300/CBP could be recruited to the promoter of CD274 (encoding PD-L1) by the transcription factor IRF-1, which induced the acetylation of Histone H3 at CD274 promoter followed by the transcription of CD274. A485, a p300/CBP inhibitor, abrogated this process and cut off the secretion of exosomal PD-L1 by blocking the transcription of CD274, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. This finding reports a new mechanism of how cancer cells regulate PD-L1 expression through epigenetic factors and provides a novel therapeutic approach to enhance the efficacy of immune checkpoint inhibitors treatment.

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Fig. 1: Class I HDACs inhibition increased PD-L1 expression in metastatic PCa cells.
Fig. 2: Upregulated PD-L1 by HDAC inhibition was due to the increased CD274 transcription.
Fig. 3: p300 was involved in PD-L1 expression in PCa cells.
Fig. 4: IRF-1 was involved in p300/CBP-induced PD-L1 expression in PCa cells.
Fig. 5: PD-L1 expression was correlated with p300/CBP in PCa patients.
Fig. 6: PD-L1 was correlated with tumor progression and tumor purity in prostate adenocarcinoma.
Fig. 7: p300/CBP inhibition enhanced the efficacy of anti-PD-L1 treatment in PCa.
Fig. 8: A working model of how p300/CBP inhibition enhanced the efficacy of PD-L1 blockade.

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Acknowledgements

This work was supported by NIH grants R01 CA157429 (XL), R01 CA192894 (XL), R01 CA196835 (XL), and R01 CA196634 (XL). 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). We thank Heather Russell-Simmons at Research Communications Office of Markey Cancer Center for proof-reading of the paper.

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

    Jinghui Liu, Changkun Huang, Yanquan Zhang, Xiongjian Rao, Yifan Kong, Chaohao Li, Zhuangzhuang Zhang & Xiaoqi Liu

  2. Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA

    Daheng He, Jinpeng Liu & Chi Wang

  3. Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA

    Lijun Cheng

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

    Karrie Jones, Dana Napier, Eun Y. Lee, Chi Wang & Xiaoqi Liu

  5. Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, 40536, USA

    Eun Y. Lee

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Liu, J., He, D., Cheng, L. et al. p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer. Oncogene 39, 3939–3951 (2020). https://doi.org/10.1038/s41388-020-1270-z

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