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Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer
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Abstract
Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4 + T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.
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“lineage tracing analysis of perivascular fibroblasts, expressing the transcription factor Gli1, showed this population expands to form nearly half of pre-CAFs in PanINs and CAFs in cancer”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [144]
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“parenchymal fibroblasts, expressing Hoxb6 do not expand during carcinogenesis144”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [144]
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Metadata
- Authors
- Huang, H., Wang, Z., Zhang, Y., Pradhan, R. N., Ganguly, D., Chandra, R., Murimwa, G., Wright, S., Gu, X., Maddipati, R., Müller, S., Turley, S. J., & Brekken, R. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of California San Diego (US)
- Genentech (US)
- Corresponding author
- Huang, Huocong
- Brekken, Rolf A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 40
- Issue
- 6
- Pages
- 656-673.e7
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC9197998
- OpenAlex
- W4229052987
- Cited by
- 542
- References
- 62
- Citations by year
- 2026: 112 · 2025: 158 · 2024: 144 · 2023: 80 · 2022: 41
- FWCI
- 44.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA210181, CA243577, CA252009)
- Burroughs Wellcome Fund
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- mesothelial cells, regulatory T cells, pancreatic cancer, tumor immune evasion, mesothelin, interleukin-1, TGF-beta, MHC class II, CD4+ T cell tolerance, lineage tracing, cancer immunotherapy
- MeSH terms
- Cancer-Associated Fibroblasts, Fibroblasts, Humans, Pancreatic Neoplasms, Transforming Growth Factor beta, T-Lymphocytes, Regulatory
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