Data from FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

• DOI: 10.1158/0008-5472.c.6508205.v1
• Publication Date: 2023-03-31T22:39:51Z
• Authors: Xuguang Yang; Yuli Lin; Yinghong Shi; Bingji Li; Weiren Liu; Wei Yin; Yongjun Dang; Yiwei Chu; Jia Fan; Rui He
• Keywords: Tumor progression; Desmoplasia; Cancer-Associated Fibroblasts

<div>Abstract<p>Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression not fully understood. Here, we show that fibroblast activation protein (FAP) triggers induction a CAF subset with an inflammatory phenotype directed by STAT3 and inflammation-associated expression signature marked CCL2 upregulation. Enforcing FAP in normal was sufficient endow them similar FAP<sup>+</sup>CAFs. We identified as persistent activator fibroblastic through uPAR-dependent FAK–Src–JAK2 signaling pathway. In murine liver model, found FAP<sup>+</sup>CAFs were major source STAT3–CCL2 this setting promoted growth enhancing recruitment myeloid-derived suppressor cells (MDSC). The receptor CCR2 expressed on circulating MDSCs tumor-bearing subjects FAP<sup>+</sup>CAF-mediated promotion MDSC abrogated Ccr2-deficient mice. Clinically, observed positive correlation between stromal FAP, p-STAT3, human intrahepatic cholangiocarcinoma, highly aggressive cancer dense desmoplastic stroma, where elevated levels predicted poor survival outcome. Taken together, our results showed how FAP–STAT3–CCL2 CAFs program component microenvironment, which may have particular significance desmoplasia-associated cancers. <i>Cancer Res; 76(14); 4124–35. ©2016 AACR</i>.</p></div>