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

By Xuguang Yang, Yuli Lin, Yinghong Shi, Bingji Li, Weiren Liu, W. Yin, Yongjun Dang, Y. Chu, Jia Fan, R. He. Cancer Research, 2016

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

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/6bcaf61c21649101c7f1c2faa28b1d68ba59040f

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Citations in the corpus

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “Subsequently, the importance of the CXCL12 signaling pathway in the regulation of tumor-infiltrating CD8 + T cell migration induced by FAP + CAFs, has been confirmed in several reports [224, 225].”
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. (2018, neutral): “In addition, CAFs have been shown to contribute to drug resistance (Straussman et al., 2012; Paulsson et al., 2017) and to reduce anti-tumor immunity (Kraman et al., 2010; Tan et al., 2011; Feig et al., 2013; Denton et al., 2014; Ruhland et al., 2016; Yang et al., 2016).”