EBF1-COX4I2信号轴促进癌相关成纤维细胞（CAFs）表现出肌纤维母细胞样表型，并与免疫抑制微环境相关

EBF1-COX4I2 signaling axis promotes a myofibroblast-like phenotype in cancer-associated fibroblasts (CAFs) and is associated with an immunosuppressive microenvironment

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INTERNATIONAL IMMUNOPHARMACOLOGY

影响因子:4.7

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

DOI: 10.1016/j.intimp.2024.112666

摘要

由于免疫微环境（TME）的免疫抑制，免疫治疗在结直肠癌（CRC）中的反应率有限。通过转录组测序、临床标本及功能实验，我们鉴定出一类具有独特特征的CAF亚群（COX4I2+），该亚群表现出线粒体呼吸受抑制和糖酵解增强。通过生物信息学预测和荧光素酶报告试验，我们发现EBF1可以上游调控COX4I2的转录。COX4I2+ CAF在功能和表型上类似肌纤维母细胞，是纤维化TME形成的重要因素，并能激活巨噬细胞的M2表型。体外实验显示，COX4I2+ CAF通过阻断CD8+ T细胞的浸润和诱导其功能障碍，促进免疫抑制性TME。利用多个独立队列分析，我们还发现CRC患者的免疫治疗反应率与肿瘤中COX4I2的表达密切相关。结果表明，激活EBF1-COX4I2轴的CAF亚群可作为靶点，改善癌症免疫治疗效果。

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.