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溴结构域和末端结构域蛋白抑制可提高肝细胞癌的免疫治疗疗效。

Bromo- and extraterminal domain protein inhibition improves immunotherapy efficacy in hepatocellular carcinoma.

机构信息

Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.

Cancer Center, Zhejiang University, Hangzhou, China.

出版信息

Cancer Sci. 2020 Oct;111(10):3503-3515. doi: 10.1111/cas.14588. Epub 2020 Aug 17.

DOI:10.1111/cas.14588
PMID:32726482
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7540980/
Abstract

Hepatocellular carcinoma (HCC) represents the majority of liver cancer and is the fourth most common cause of cancer-related death. Although advances in molecular targeted therapy have shown promise, none of these agents has yet demonstrated significant clinical benefit. Bromo- and extraterminal domain (BET) protein inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This study found that BET protein inhibition did not effectively suppress the progression of HCC, using a transgenic HCC mouse model. Mechanistically, the BET protein inhibitor JQ1 upregulated the expression of programmed cell death-ligand 1 (PD-L1) on the plasma membrane in vivo and in vitro. Moreover, JQ1 enhanced the expression of Rab8A, which upregulated the expression of PD-L1 on the plasma membrane. This study also showed that JQ1 combined with anti-PD-L1 Ab effectively suppressed HCC progression, and this benefit was obtained by enhancing the activation and cytotoxic capabilities of CD8 T cells. These results revealed the crucial role and regulation of BET protein inhibition on the expression of PD-L1 in HCC. Thus, combining BET protein inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC.

摘要

肝细胞癌（HCC）是肝癌的主要类型，也是癌症相关死亡的第四大常见原因。尽管分子靶向治疗的进展显示出了一定的前景，但这些药物都尚未显示出显著的临床获益。Bromo- 和末端结构域（BET）蛋白抑制剂被认为是 HCC 的潜在治疗药物，但它们的生物学活性仍不清楚。本研究使用转基因 HCC 小鼠模型发现，BET 蛋白抑制剂 JQ1 并不能有效抑制 HCC 的进展。在机制上，BET 蛋白抑制剂 JQ1 在体内和体外均上调了质膜上程序性细胞死亡配体 1（PD-L1）的表达。此外，JQ1 增强了 Rab8A 的表达，从而上调了质膜上 PD-L1 的表达。本研究还表明，JQ1 联合抗 PD-L1 Ab 可有效抑制 HCC 进展，这是通过增强 CD8 T 细胞的激活和细胞毒性能力获得的。这些结果揭示了 BET 蛋白抑制对 HCC 中 PD-L1 表达的关键作用和调控。因此，BET 蛋白抑制与免疫检查点阻断相结合为 HCC 提供了一种有效的治疗方法。

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