FAP Promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 Signaling

Xuguang Yang, Yuli Lin, Yinghong Shi, Bingji Li, Weiren Liu, Wei Yin, Yongjun Dang, Yiwei Chu, Jia Fan, Rui He

Research output: Contribution to journalArticlepeer-review

Abstract

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 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, +-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.

Original languageEnglish (US)
Pages (from-to)4124-4135
Number of pages12
JournalCancer Research
Volume76
Issue number14
DOIs
StatePublished - Jul 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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