Cited by 542Pancreatic and Hepatic Oncology ResearchCancer Immunotherapy and BiomarkersTGF-β signaling in diseases

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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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Huang, Huocong, Wang, Zhaoning, Zhang, Yuqing, Pradhan, Rachana N., Ganguly, Debolina, Chandra, Raghav, Murimwa, Gilbert, Wright, Steven, Gu, Xiaowu, Maddipati, Ravikanth, Müller, Sören, Turley, Shannon J., Brekken, Rolf A.·2022·Cancer Cell

DOI 10.1016/j.ccell.2022.04.011PMC PMC9197998

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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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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: Huang, Huocong
Wang, Zhaoning
Zhang, Yuqing
Pradhan, Rachana N.
Ganguly, Debolina
Chandra, Raghav
Murimwa, Gilbert
Gu, Xiaowu
Maddipati, Ravikanth
Müller, Sören
Turley, Shannon J.
Brekken, Rolf A.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2022-06
Volume: 40
Issue: 6
Pages: 656-673.e7
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2022.04.011
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
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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Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer

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