BET Protein Inhibition Improves Immunotherapy Efficacy in Hepatocellular Carcinoma.

Liu, Chen; Miao, Xiaolong; Wang, Yao; Wen, Liang; Cheng, Xiawei; Kong, Deqiang; Zhao, Pengwei; Song, Dandan; Wang, Xinyi; Ding, Xianfeng; Xia, Hongguang; Wang, Weilin; Sun, Qiming; Gong, Weihua

Hepatocellular carcinoma (HCC) represents the majority of liver cancer and the fourth most common cause of cancer-related death. Although advances in targeted molecular targeted therapy have shown promise, none of these agents have yet demonstrated significant clinical benefits. Bromo- and extraterminal domain (BET) proteins inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This present study found that BET proteins inhibition did not effectively suppress the progression of HCC using a transgenic HCC mouse model. Mechanistically, the BET proteins inhibitor JQ1 upregulated the expression of 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 proteins inhibition on the expression of PD-L1 in HCC. Thus, combining BET proteins inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC.