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.

中文翻译：

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p300/CBP 抑制增强了程序性死亡配体 1 阻断治疗在前列腺癌中的疗效。

通过治疗性抗体阻断程序性死亡配体 1 (PD-L1) 已被证明是癌症治疗中一种很有前景的策略，但对包括前列腺癌 (PCa) 在内的多种癌症的临床反应是有限的。肿瘤细胞通过外泌体或剪接变体分泌 PD-L1，这被描述为在包括 PCa 在内的多种癌症中抵抗 PD-L1 阻断疗法的新机制。这表明切断 PD-L1 的分泌或表达可能会提高 PD-L1 阻断疗法在 PCa 治疗中的反应率。在这里，我们报告了小分子 p300/CBP 抑制剂对 p300/CBP 的抑制，通过阻断内在和 IFN-γ 诱导的 PD-L1 表达，显着增强了 PCa 同基因模型中 PD-L1 阻断治疗的功效。从机制上讲，p300/CBP 可以被转录因子 IRF-1 募集到 CD274（编码 PD-L1）的启动子，从而诱导 CD274 启动子处组蛋白 H3 的乙酰化，然后是 CD274 的转录。A485 是一种 p300/CBP 抑制剂，它通过阻断 CD274 的转录来消除这一过程并切断外泌体 PD-L1 的分泌，CD274 与抗 PD-L1 抗体结合重新激活 T 细胞功能以进行肿瘤攻击。这一发现报告了癌细胞如何通过表观遗传因子调节 PD-L1 表达的新机制，并提供了一种新的治疗方法来提高免疫检查点抑制剂治疗的疗效。通过阻断 CD274 的转录，废除了这一过程并切断了外泌体 PD-L1 的分泌，CD274 与抗 PD-L1 抗体结合重新激活 T 细胞功能以进行肿瘤攻击。这一发现报告了癌细胞如何通过表观遗传因子调节 PD-L1 表达的新机制，并提供了一种新的治疗方法来提高免疫检查点抑制剂治疗的疗效。通过阻断 CD274 的转录，废除了这一过程并切断了外泌体 PD-L1 的分泌，CD274 与抗 PD-L1 抗体结合重新激活 T 细胞功能以进行肿瘤攻击。这一发现报告了癌细胞如何通过表观遗传因子调节 PD-L1 表达的新机制，并提供了一种新的治疗方法来提高免疫检查点抑制剂治疗的疗效。