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Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis
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Abstract
Regulatory T cells (Treg) are abundant in human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin–expressing fibroblasts. Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression, and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathologic CD4+ T-cell responses. Our data point to new mechanisms regulating fibroblast differentiation in pancreatic cancer and support the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis. Significance: Here, we describe an unexpected cross-talk between Tregs and fibroblasts in pancreatic cancer. Treg depletion resulted in differentiation of inflammatory fibroblast subsets, in turn driving infiltration of myeloid cells through CCR1, thus uncovering a potentially new therapeutic approach to relieve immunosuppression in pancreatic cancer. See related commentary by Aykut et al., p. 345. This article is highlighted in the In This Issue feature, p. 327
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“Other T cell populations within the TME have all been noted to play protumorigenic roles, including Th17, Th22, CD4, and γδ T cells188–191”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [191]
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“Additionally, this study analyzed tissue levels and found that the positive effect of Tregs depletion, which results in an increase in CD8+ T cells, was negated by an increase in other CD4+ Th cells, immunosuppressive myeloid cells, and fibroblast populations, ultimately failing to inhibit tumor growth [116, 131] (Fig. 2E).”
From Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review (2024) · cites this paper as [116]
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Metadata
- Authors
- Zhang, Y., Lazarus, J., Steele, N. G., Yan, W., Lee, H.-J., Nwosu, Z. C., Halbrook, C. J., Menjivar, R. E., Kemp, S. B., Sirihorachai, V. R., Velez-Delgado, A., Donahue, K., Carpenter, E. S., Brown, K. L., Irizarry-Negron, V., Nevison, A. C., Vinta, A., Anderson, M. A., Crawford, H. C., Lyssiotis, C. A., Frankel, T. L., Bednar, F., & Pasca di Magliano, M.
- Affiliations
- University of Michigan (US)
- 1Department of Surgery, University of Michigan, Ann Arbor, Michigan.
- Corresponding author
- Zhang, Yaqing
- Bednar, Filip
- ORCID
- Zhang, Yaqing
- Lazarus, Jenny
- Steele, Nina G.
- Yan, Wei
- Lee, Ho-Joon
- Nwosu, Zeribe C.
- Halbrook, Christopher J.
- Menjivar, Rosa E.
- Kemp, Samantha B.
- Sirihorachai, Veerin R.
- Velez-Delgado, Ashley
- Donahue, Katelyn
- Carpenter, Eileen S.
- Brown, Kristee L.
- Irizarry-Negron, Valerie
- Anderson, Michelle A.
- Crawford, Howard C.
- Lyssiotis, Costas A.
- Frankel, Timothy L.
- Bednar, Filip
- Pasca di Magliano, Marina
- Venue
- Cancer Discovery
- Published
- 2020-03-01
- Volume
- 10
- Issue
- 3
- Pages
- 422-439
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7224338
- OpenAlex
- W3000274143
- Cited by
- 385
- References
- 73
- Citations by year
- 2026: 34 · 2025: 49 · 2024: 73 · 2023: 62 · 2022: 66 · 2021: 70 · 2020: 30
- FWCI
- 20.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (R01CA151588, R01CA198074, U01CA224145, P30CA046592, R50CA232985, 3-P30-CA-046592-28-S2, K08CA201581, T32-CA009676)
- American Cancer Society (Postdoctoral Award)
- University of Michigan Medical School (Michigan Postdoctoral Pioneer Program)
- HHS | NIH | National Institute of General Medical Sciences (T32-GM007315, T32-GM113900)
- Horace H. Rackham School of Graduate Studies, University of Michigan (Rackham Merit Fellowship)
- Association of Academic Surgery (Joel Roslyn Award)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- regulatory T cells, Treg depletion, pancreatic cancer, tumor microenvironment, immunosuppression, TGF-beta, cancer-associated fibroblasts, CCR1, myeloid cell recruitment, CD4+ T cells, pancreatic carcinogenesis, tumor progression
- MeSH terms
- Animals, Disease Models, Animal, Fibroblasts, Humans, Pancreas, Pancreatic Neoplasms, Transforming Growth Factor beta, Chemokines, CC, T-Lymphocytes, Regulatory, Mice, Receptors, CCR1, Chemokine CCL3, Chemokine CCL8, Tumor Microenvironment, Carcinogenesis
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