Liu et al. probed epigenetic regulators of PD-L1 in prostate cancer. Class I histone deacetylase inhibition boosted histone acetylation and transcription of the PD-L1 encoding gene CD274. Histone acetyltransferases p300 and CBP associated with transcription factor IRF-1 to drive CD274 transcription, and p300/CBP inhibition blocked cellular and exosomal PD-L1. In a prostate cancer model, anti-PD-L1 therapy alone was ineffective but slowed tumor growth with p300/CBP inhibition. In human prostate cancer datasets, expression of genes encoding p300 and CBP correlated with CD274 expression, cancer progression, and reduced patient survival.
Contributed by Alex Najibi
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-gamma-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.
Author Info: (1) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (2) Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, U
Author Info: (1) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (2) Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA. (3) Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. (4) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (5) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (6) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (7) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (8) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (9) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. (10) Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA. (11) Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. (12) Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. (13) Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, 40536, USA. (14) Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. (15) Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA. Xiaoqi.Liu@uky.edu. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. Xiaoqi.Liu@uky.edu.
