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CD4+ T Lymphocyte Ablation Prevents Pancreatic Carcinogenesis in Mice
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Abstract
Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer. Cancer Immunol Res; 2(5); 423–35. ©2014 AACR.
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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 [190]
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Immunity, Inflammation, and Cancer
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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
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CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans
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Self-citationAdaptive immunity maintains occult cancer in an equilibrium state
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Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A., Teinor, J. A., Belleau, P., Biffi, G., Lucito, M. S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0094 · Cited by 2,241
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
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Steele, N. G., Carpenter, E. S., Kemp, S. B., Sirihorachai, V. R., The, S., Delrosario, L., Lazarus, J., Amir, E.-A. D., Gunchick, V., Espinoza, C. E., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-00121-4 · Cited by 556
Self-citationGenetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
Winograd, R., Byrne, K. T., Evans, R. A., Odorizzi, P. M., Meyer, A. R. L., Bajor, D. L., Clendenin, C., Stanger, B. Z., Furth, E. E., Wherry, E. J., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0215 · Cited by 459
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Metadata
- Authors
- Zhang, Y., Yan, W., Mathew, E., Bednar, F., Wan, S., Collins, M. A., Evans, R. A., Welling, T. H., Vonderheide, R. H., & di Magliano, M. P.
- Affiliations
- University of Michigan (US)
- Authors' Affiliations: Departments of 1Surgery, 2Pathology, and 3Cell and Developmental Biology, 4Michigan Center for Translational Pathology, 5Program in Cellular and Molecular Biology; 6Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; 7Abramson Family Cancer Research Institute; and 8Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Venue
- Cancer Immunology Research
- Published
- 2014-05-01
- Volume
- 2
- Issue
- 5
- Pages
- 423-435
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC4160804
- OpenAlex
- W2139909490
- Cited by
- 102
- References
- 41
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 12 · 2023: 7 · 2022: 16 · 2021: 6 · 2020: 10 · 2019: 12 · 2018: 5 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 4
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University
- National Cancer Institute (R01CA151588, K08CA151414, R01CA169123)
- National Institute of General Medical Sciences (T32GM007315)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, T32DK094775)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (5-T32-HD007515, T32HD007505)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- CD4+ T cells, pancreatic carcinogenesis, pancreatic intraepithelial neoplasia, oncogenic KRAS, CD8+ T cells, immunosuppressive tumor microenvironment, immune tolerance, pancreatitis, immunomodulatory therapy
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Lymphocyte Depletion, Pancreatic Neoplasms, Pancreatitis, CD4-Positive T-Lymphocytes, T-Lymphocyte Subsets, Proto-Oncogene Proteins p21(ras), Apoptosis, Mice, Knockout, Lymphocyte Count, Mice
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