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

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.

• Authors: Jinghui Liu, Daheng He, Lijun Cheng, Changkun Huang, Yanquan Zhang, Xiongjian Rao, Yifan Kong, Chaohao Li, Zhuangzhuang Zhang, Jinpeng Liu, Karrie Jones, Dana Napier, Eun Y Lee, Chi Wang, Xiaoqi Liu
• Journal: Oncogene (Oncogene) Vol. 39 Issue 19 Pg. 3939-3951 (05 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32203167 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• B7-H1 Antigen
• CD274 protein, human
• IFNG protein, human
• Interferon Regulatory Factor-1
• Small Molecule Libraries
• Interferon-gamma
• p300-CBP Transcription Factors

Topics

• Antibodies, Monoclonal (immunology, pharmacology)
• B7-H1 Antigen (antagonists & inhibitors, genetics)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunotherapy (methods)
• Interferon Regulatory Factor-1 (genetics)
• Interferon-gamma (genetics)
• Male
• Prostatic Neoplasms (genetics, immunology, pathology, therapy)
• Small Molecule Libraries (pharmacology)
• T-Lymphocytes (immunology)
• p300-CBP Transcription Factors (antagonists & inhibitors, genetics)