State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Cancer Lett. 2024 Jan 1;580:216483. doi: 10.1016/j.canlet.2023.216483. Epub 2023 Nov 14.
Cellular plasticity and immune escape are synergistic drivers of tumor colonization in metastatic organs. Activation of protease-activated receptor 2 (PAR2) signaling promotes metastasis of colorectal carcinoma (CRC). The role of PAR2 in regulating the immune microenvironment and cancer progression remains unclear. We demonstrated that the regulation of liver metastasis by PAR2 requires a competent immune system. PAR2 knockdown enhanced liver infiltration of activated CD8 T cells prior to metastatic foci formation in an interferon receptor-dependent manner. PAR2 depletion increased interferon (IFN)-β production via the cGAS-STING and RIG-1 pathways. PAR2 inhibition increased mitochondrial permeability and cytosolic accumulation of mitochondrial DNA, which was reversed by Bcl-xL expression. Strikingly, shRNA against PAR2 with an immune checkpoint blocker (ICB) acted synergistically to suppress liver metastasis. Analysis of single-cell sequence data and 24 paired samples confirmed the regulatory effect of PAR2 on the metastatic immune environment in human CRC. Therefore, PAR2 signaling is involved in stabilizing the mitochondrial membrane and regulating the immune microenvironment through IFN-β during liver metastasis in CRC. The synergistic effect of the PAR2 inhibitor and ICB provides a potential therapeutic strategy for metastatic CRC treatment.
细胞可塑性和免疫逃逸是肿瘤在转移器官定植的协同驱动因素。蛋白酶激活受体 2（PAR2）信号的激活促进结直肠癌（CRC）的转移。PAR2 在调节免疫微环境和癌症进展中的作用仍不清楚。我们证明，PAR2 对肝转移的调节需要一个功能健全的免疫系统。PAR2 敲低以干扰素受体依赖的方式增强了转移灶形成前活化的 CD8 T 细胞在肝脏中的浸润。PAR2 耗竭通过 cGAS-STING 和 RIG-1 途径增加干扰素（IFN）-β的产生。PAR2 抑制增加了线粒体通透性和线粒体 DNA 的胞质积累，这可以通过 Bcl-xL 表达来逆转。引人注目的是，针对 PAR2 的 shRNA 与免疫检查点抑制剂（ICB）协同作用以抑制肝转移。单细胞序列数据和 24 对配对样本的分析证实了 PAR2 对人 CRC 转移免疫环境的调节作用。因此，PAR2 信号通过 IFN-β 在 CRC 肝转移过程中参与稳定线粒体膜并调节免疫微环境。PAR2 抑制剂和 ICB 的协同作用为转移性 CRC 的治疗提供了一种潜在的治疗策略。
