Cited by 389Pancreatic and Hepatic Oncology ResearchTGF-β signaling in diseasesCancer Immunotherapy and Biomarkers

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Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis

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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, Nevison, Anna C., Vinta, Alekya, Anderson, Michelle A., Crawford, Howard C., Lyssiotis, Costas A., Frankel, Timothy L., Bednar, Filip, Pasca di Magliano, Marina·2020·Cancer Discovery

DOI 10.1158/2159-8290.cd-19-0958PMC PMC7224338

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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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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
Publisher: American Association for Cancer Research (AACR)
Published: 2020-03-01
Volume: 10
Issue: 3
Pages: 422-439
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-19-0958
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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Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis

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