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


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.


  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  2. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol. 2011;8:12–23.

    Article  CAS  Google Scholar 

  3. Claessens F, Helsen C, Prekovic S, Van den Broeck T, Spans L, Van Poppel H, et al. Emerging mechanisms of enzalutamide resistance in prostate cancer. Nat Rev Urol. 2014;11:712–6.

    Article  CAS  Google Scholar 

  4. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–65.

    Article  Google Scholar 

  5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  Google Scholar 

  6. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Investig. 2015;125:3384–91.

    Article  Google Scholar 

  7. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6.

    Article  CAS  Google Scholar 

  8. Gong B, Kiyotani K, Sakata S, Nagano S, Kumehara S, Baba S, et al. Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer. J Exp Med. 2019;216:982–1000.

    Article  CAS  Google Scholar 

  9. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell. 2019;177:414–27.e413.

    Article  CAS  Google Scholar 

  10. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    CAS  Google Scholar 

  11. Nebbioso A, Tambaro FP, Dell’Aversana C, Altucci L. Cancer epigenetics: moving forward. PLoS Genet. 2018;14:e1007362.

    Article  Google Scholar 

  12. Jin L, Garcia J, Chan E, de la Cruz C, Segal E, Merchant M, et al. Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer. Cancer Res. 2017;77:5564–75.

    Article  CAS  Google Scholar 

  13. Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D, Digiammarino EL, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017;550:128–32.

    Article  CAS  Google Scholar 

  14. Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.

    Article  CAS  Google Scholar 

  15. Yang YA, Yu J. EZH2, an epigenetic driver of prostate cancer. Protein Cell. 2013;4:331–41.

    Article  CAS  Google Scholar 

  16. Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein acetylation. Biochim Biophys Acta. 2016;1864:1372–401.

    Article  CAS  Google Scholar 

  17. Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep. 2016;16:2829–37.

    Article  CAS  Google Scholar 

  18. Zhong J, Ding L, Bohrer LR, Pan Y, Liu P, Zhang J, et al. p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis. Cancer Res. 2014;74:1870–80.

    Article  CAS  Google Scholar 

  19. Haeussler M, Zweig AS, Tyner C, Speir ML, Rosenbloom KR, Raney BJ, et al. The UCSC genome browser database: 2019 update. Nucleic Acids Res. 2019;47:D853–8.

  20. Smithy JW, Moore LM, Pelekanou V, Rehman J, Gaule P, Wong PF, et al. Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma. J Immunother Cancer. 2017;5:25.

    Article  Google Scholar 

  21. Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189–201.

    Article  CAS  Google Scholar 

  22. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77:e108–e110.

    Article  CAS  Google Scholar 

  23. Coelho MA, de Carne Trecesson S, Rana S, Zecchin D, Moore C, Molina-Arcas M, et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity. 2017;47:1083–99 e1086.

    Article  CAS  Google Scholar 

  24. Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, et al. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem. 2000;275:20853–60.

    Article  CAS  Google Scholar 

  25. Martin AM, Nirschl TR, Nirschl CJ, Francica BJ, Kochel CM, van Bokhoven A, et al. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 2015;18:325–32.

    Article  CAS  Google Scholar 

  26. Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The immune checkpoint regulator PD-L1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2016;22:1969–77.

    Article  CAS  Google Scholar 

  27. Calagua C, Russo J, Sun Y, Schaefer R, Lis R, Zhang Z, et al. Expression of PD-L1 in hormone-naive and treated prostate cancer patients receiving neoadjuvant abiraterone acetate plus prednisone and leuprolide. Clin Cancer Res. 2017;23:6812–22.

    Article  CAS  Google Scholar 

  28. Massari F, Ciccarese C, Calio A, Munari E, Cima L, Porcaro AB, et al. Magnitude of PD-1, PD-L1 and T lymphocyte expression on tissue from castration-resistant prostate adenocarcinoma: an exploratory analysis. Target Oncol. 2016;11:345–51.

    Article  Google Scholar 

  29. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  Google Scholar 

  30. Mahoney KM, Shukla SA, Patsoukis N, Chaudhri A, Browne EP, Arazi A, et al. A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression. Cancer Immunol Immunother. 2019;68:421–32.

    Article  CAS  Google Scholar 

  31. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–89.

    Article  CAS  Google Scholar 

  32. Li Y, Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med. 2016;6:a026831:1–34.

  33. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18,1414:1–25.

  34. Kaushik D, Vashistha V, Isharwal S, Sediqe SA, Lin MF. Histone deacetylase inhibitors in castration-resistant prostate cancer: molecular mechanism of action and recent clinical trials. Ther Adv Urol. 2015;7:388–95.

    Article  CAS  Google Scholar 

  35. Liu J, Wang B, Huang P, Wang H, Xu K, Wang X, et al. Microcystin-LR promotes cell proliferation in the mice liver by activating Akt and p38/ERK/JNK cascades. Chemosphere. 2016;163:14–21.

    Article  CAS  Google Scholar 

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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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Correspondence to Xiaoqi Liu.

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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).

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