安非雷古林
癌症研究
癌相关成纤维细胞
肿瘤微环境
癌变
免疫疗法
生物
表皮生长因子受体
癌症
免疫系统
免疫学
细胞生物学
化学
遗传学
作者
Runzi Sun,Hongyu Zhao,David Shihong Gao,Andrew Ni,Haochen Li,Lujia Chen,Xinghua Lu,Kong Chen,Binfeng Lu
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2023-08-25
卷期号:9 (34)
被引量:10
标识
DOI:10.1126/sciadv.add7399
摘要
Regulatory T (T reg ) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives T reg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1 + T reg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in T reg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)–epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1 + T reg cells and CAFs. We further demonstrated that the AREG/EGFR axis enables T reg cells to promote a profibrotic and immunosuppressive functional state of CAFs. Moreover, AREG mAbs and IL-33 concertedly inhibited tumor growth. Our study reveals a previously unidentified AREG/EGFR-mediated T reg /CAF coupling that controls the bifurcation of fibroblast functional states and is a critical barrier for cancer immunotherapy.
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