靶向 VCP 可增强结直肠癌的免疫检查点治疗。
Targeting VCP potentiates immune checkpoint therapy for colorectal cancer.
发表日期：2023 Oct 21
作者：
Fang Wang, Qi Qi, Baifu Qin, Yiwei Wang, Youwei Huang, Qing Li, Xi Shen, Xiangyu Wang, Shangqi Yang, Guopeng Pan, Jiahong Chen, Zixi Qin, Xueqin Chen, Yuqing Yang, Yuequan Zeng, Jun Liu, Yuqin Li, Ying Li, Zexiong Cheng, Xi Lin, Fan Xing, Yubo Zhang, Guocai Wang, Kai Li, Zhenyou Jiang, Haipeng Zhang
来源：
Cell Death & Disease
摘要：
免疫检查点阻断疗法对大多数结直肠癌（CRC）患者仍然无效。免疫原性细胞死亡（ICD）能够释放关键的免疫刺激信号，以驱动有效的抗肿瘤免疫，这可用于增强免疫检查点抑制剂的作用。在这里，我们发现抑制缬洛辛蛋白 (VCP) 会引发结直肠癌 (CRC) 中的 ICD。同时，VCP 抑制剂上调 PD-L1 表达并损害体内抗肿瘤免疫。从机制上讲，VCP 以 JAK1 依赖性方式转录调节 PD-L1 表达。 VCP 抑制剂与抗 PD1 组合可重塑肿瘤免疫微环境并减少 CRC 小鼠模型中的肿瘤生长。溶瘤病毒的添加进一步增强了联合方案的治疗活性。我们的研究揭示了 VCP 调节 PD-L1 表达的分子机制，并表明抑制 VCP 有可能提高 CRC 免疫治疗的疗效。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.