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FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling
Published version of a preprint
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(+)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 hav…
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“In addition, CAFs secrete substantial amounts of growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CC-chemokine ligand 2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape 20-22.”
From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [21]
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Metadata
- Authors
- Yang, X., Lin, Y., Shi, Y., Li, B., Liu, W., Yin, W., Dang, Y., Chu, Y., Fan, J., & He, R.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Venue
- Cancer Research
- Published
- 2016-07-14
- Volume
- 76
- Issue
- 14
- Pages
- 4124-4135
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2400022769
- Cited by
- 748
- References
- 44
- Citations by year
- 2026: 66 · 2025: 101 · 2024: 107 · 2023: 115 · 2022: 91 · 2021: 95 · 2020: 67 · 2019: 47 · 2018: 31 · 2017: 25 · 2016: 3
- FWCI
- 19.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NSFC (813220437, 81471555, 81272389)
- National Key Sci-Tech Project (2012ZX10002011-002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- fibroblast activation protein, cancer-associated fibroblasts, tumor microenvironment, STAT3 signaling, MCP-1, CCR2, myeloid-derived suppressor cells, uPAR, desmoplasia, intrahepatic cholangiocarcinoma, liver cancer, immunosuppression, tumor stroma
- MeSH terms
- Cancer-Associated Fibroblasts, Fibroblast Activation Protein Alpha, Animals, Cell Movement, Female, Immune Tolerance, Membrane Proteins, Mice, Inbred C57BL, Endopeptidases, Serine Endopeptidases, Signal Transduction, Gelatinases, Chemokine CCL2, STAT3 Transcription Factor, Mice, Focal Adhesion Protein-Tyrosine Kinases, Janus Kinase 2, Receptors, Urokinase Plasminogen Activator, Tumor Microenvironment
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