EBF1-COX4I2信号轴促进癌症相关的成纤维细胞（CAF）中的肌成纤维细胞样表型，并与免疫抑制微环境有关
EBF1-COX4I2 signaling axis promotes a myofibroblast-like phenotype in cancer-associated fibroblasts (CAFs) and is associated with an immunosuppressive microenvironment
影响因子:4.70000
分区:医学2区 / 药学2区 免疫学3区
发表日期:2024 Sep 30
作者:
Jie-Pin Li, Yuan-Jie Liu, Shuang-Shuang Wang, Zhi-Hua Lu, Qian-Wen Ye, Jin-Yong Zhou, Xi Zou, Yu-Gen Chen
摘要
由于免疫抑制肿瘤微环境（TME），免疫疗法的结直肠癌（CRC）的反应率有限。结合了转录组测序，临床样本和功能实验，我们确定了一组独特的CAF亚群（COX4I2+）以及抑制的线粒体呼吸和增强的糖酵解。通过生物信息学预测和荧光素酶报告基准测定，我们确定EBF1可以在上游调节Cox4i2转录。 COX4I2+CAF在功能和表型上类似于肌纤维细胞，对于纤维化TME的形成很重要，并且能够激活巨噬细胞的M2表型。体外实验表明，COX4I2+CAFS通过阻止CD8+T细胞浸润并诱导CD8+T细胞功能障碍来促进免疫抑制TME。使用多个独立队列，我们还发现CRC患者的免疫疗法反应率与肿瘤中COX4I2的表达之间存在很强的相关性。我们的结果确定了以EBF1-COX4I2轴激活为特征的CAF亚群，并且可以针对这组CAF来改善癌症免疫疗法的结果。
Abstract
Immunotherapy has limited response rates in colorectal cancer (CRC) due to an immunosuppressive tumor microenvironment (TME). Combining transcriptome sequencing, clinical specimens, and functional experiments, we identified a unique group of CAF subpopulations (COX4I2 + ) with inhibited mitochondrial respiration and enhanced glycolysis. Through bioinformatics predictions and luciferase reporter assays, we determined that EBF1 can upstreamly regulate COX4I2 transcription. COX4I2 + CAFs functionally and phenotypically resemble myofibroblasts, are important for the formation of the fibrotic TME, and are capable of activating the M2 phenotype of macrophages. In vitro experiments demonstrated that COX4I2 + CAFs promote immunosuppressive TME by blocking CD8 + T cell infiltration and inducing CD8 + T cell dysfunction. Using multiple independent cohorts, we also found a strong correlation between the immunotherapy response rate of CRC patients and COX4I2 expression in their tumors. Our results identify a CAF subpopulation characterized by activation of the EBF1-COX4I2 axis, and this group of CAFs can be targeted to improve cancer immunotherapy outcomes.