Open Accessp300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer
Author(s) -
Jinghui Liu,
Daheng He,
Lijun Cheng,
Chí Huang,
Yanquan Zhang,
Xiongjian Rao,
Yifan Kong,
Chaohao Li,
Zhuangzhuang Zhang,
Jinpeng Liu,
Karrie L. Jones,
Dapier,
Eun Y. Lee,
Chi Wang,
Xiaoqi Liu
Publication year - 2020
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-020-1270-z
Subject(s) - blockade , prostate cancer , cancer research , immune checkpoint , biology , transcription factor , cancer , pd l1 , tumor microenvironment , immune system , immunology , immunotherapy , receptor , biochemistry , genetics , gene
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.