Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer
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Significance: Cancer immune evasion is well described. In some cases, this may be overcome by enhancing T-cell responses. We show that despite the presence of antitumor T cells, immunotherapeutic antibodies are ineffective in a murine pancreatic cancer model recapitulating the human disease. Removing the carcinoma-associated fibroblast (CAF) expressing fibroblast activation protein (FAP) from tumors permitted immune control of tumor growth and uncovered the efficacy of these immunotherapeutic antibodies. FAP + CAFs are the only tumoral source of chemokine (C-X-C motif) ligand 12 (CXCL12), and administering AMD3100, an inhibitor of chemokine (C-X-C motif) receptor 4, a CXCL12 receptor, also revealed the antitumor effects of an immunotherapeutic antibody and greatly diminished cancer cells. These findings may have wide clinical relevance because FAP + cells are found in almost all human adenocarcinomas.
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CAFs are the major source of CXCL12 in many tumours.
“targeting CXCL12 signalling could be considered to be targeting CAFs as they are the major source of the chemokine in many tumours121.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [121]
The paper identifies FAP+ CAFs as the principal source of CXCL12 in its pancreatic tumour model (p. 1) and reports FAP+ cells as the source in a Lewis lung carcinoma model (p. 2). It does not establish that CAFs are the major source across “many tumours”; its discussion of wider relevance is tentative (p. 4). (LLM, conf=0.86)
Experimental — accuracy not yet measuredMost studies have suggested an immunosuppressive role of CAFs.
“most studies have suggested an immunosuppressive role of CAFs121”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [121]
The paper reports immunosuppression mediated by FAP-positive CAFs in a murine pancreatic cancer model (p. 1) and mentions a previous murine tumor study with a similar finding (p. 1). It does not establish that most studies have suggested an immunosuppressive role for CAFs generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInterference with the action of CXCL12 produced by CAFs promotes T cell-mediated tumour control.
“Interference with the action of CXCL12 produced by CAFs promotes T cell-mediated tumour control16,121,122”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [121]
apCAF transcriptional profiles overlap with mesothelial cells and are postulated to derive from a mesothelial origin.
“the transcriptional profiles of apCAFs overlap with mesothelial cells150, and based on lineage tracing studies in mice have been postulated to derive from a mesothelial origin145”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [150]
Activated fibroblasts can further differentiate into myofibroblasts that express α-smooth muscle actin.
“They can further differentiate into myofibroblasts that express α-smooth muscle actin232.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [232]
FAP+ CAFs inhibited anti-tumor T cell function in gastric and pancreatic cancer, and targeting FAP+ subtypes enhanced tumor response to ICB.
“fibroblast activation protein (FAP)+ CAFs inhibited anti-tumor function of T cells in gastric cancer and pancreatic cancer and targeting these FAP+ subtypes enhanced tumor response to ICB (Feig et al., 2013).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Feig et al., 2013
CAF depletion using diphtheria toxin-based immunotherapy reduces cancer growth by increasing CD8+ Teff-cell infiltration to the TME.
“Moreover, CAF depletion using diphtheria toxin‐based immunotherapy reduced cancer growth by increasing CD8+ Teff‐cell infiltration to the TME [102].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [102]
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- Authors
- Feig, C., Jones, J. O., Kraman, M., Wells, R. J. B., Deonarine, A., Chan, D. S., Connell, C. M., Roberts, E. W., Zhao, Q., Caballero, O. L., Teichmann, S. A., Janowitz, T., Jodrell, D. I., Tuveson, D. A., & Fearon, D. T.
- Affiliations
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology (GB)
- Johns Hopkins University (US)
- Ludwig Collaborative Laboratory, Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; and
- European Bioinformatics Institute (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-11-25
- Volume
- 110
- Issue
- 50
- Pages
- 20212-20217
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3864274
- OpenAlex
- W2086834665
- Cited by
- 2,100
- References
- 28
- Citations by year
- 2026: 252 · 2025: 157 · 2024: 226 · 2023: 214 · 2022: 221 · 2021: 244 · 2020: 203 · 2019: 149 · 2018: 125 · 2017: 119 · 2016: 95 · 2015: 63 · 2014: 30
- FWCI
- 33.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK (15678)
- National Institute for Health and Care Research (CL-2011-14-007)
- Medical Research Council (MC_PC_12012)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Keywords
- pancreatic ductal adenocarcinoma, CXCL12, fibroblast activation protein, cancer-associated fibroblasts, PD-L1 blockade, CTLA-4 blockade, tumor immune evasion, tumor stroma, CXCR4 inhibition, AMD3100, CD8+ T cells, chemokine signaling, immunotherapy resistance
- MeSH terms
- Cyclams, Fibroblast Activation Protein Alpha, Analysis of Variance, Animals, Base Sequence, Benzylamines, Fibroblasts, Flow Cytometry, Fluorescent Antibody Technique, Heterocyclic Compounds, Immunohistochemistry, Immunotherapy, Membrane Proteins, Molecular Sequence Data, Pancreatic Neoplasms, Endopeptidases, Serine Endopeptidases, Sequence Analysis, RNA, Gelatinases, Tumor Escape, Carcinoma, Pancreatic Ductal, Mice, Chemokine CXCL12, Enzyme-Linked Immunospot Assay
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