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IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions
G. Mucciolo, C. Curcio, C. Roux, WY. Li, M. Capello, R. Curto, R. Chiarle, D. Giordano, MA. Satolli, R. Lawlor, A. Scarpa, P. Lukac, D. Stakheev, P. Provero, L. Vannucci, TW. Mak, F. Novelli, P. Cappello
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1915 to 6 months ago
Freely Accessible Science Journals
from 1915 to 6 months ago
PubMed Central
from 1915 to 6 months ago
Europe PubMed Central
from 1915 to 6 months ago
Open Access Digital Library
from 1915-01-15
Open Access Digital Library
from 1915-01-01
- MeSH
- Adenocarcinoma genetics pathology MeSH
- CD8-Positive T-Lymphocytes metabolism pathology MeSH
- Carcinoma, Pancreatic Ductal genetics pathology MeSH
- Cancer-Associated Fibroblasts metabolism pathology MeSH
- Forkhead Transcription Factors genetics MeSH
- Interleukin-17 genetics MeSH
- Carcinogenesis genetics MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Tumor Microenvironment genetics MeSH
- Receptors, Interleukin genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A hallmark of cancer, including pancreatic ductal adenocarcinoma (PDA), is a massive stromal and inflammatory reaction. Many efforts have been made to identify the anti- or protumoral role of cytokines and immune subpopulations within the stroma. Here, we investigated the role of interleukin-17A (IL17A) and its effect on tumor fibroblasts and the tumor microenvironment. We used a spontaneous PDA mouse model (KPC) crossed to IL17A knockout mice to show an extensive desmoplastic reaction, without impaired immune infiltration. Macrophages, especially CD80+ and T cells, were more abundant at the earlier time point. In T cells, a decrease in FoxP3+ cells and an increase in CD8+ T cells were observed in KPC/IL17A-/- mice. Fibroblasts isolated from IL17A+/+ and IL17A-/- KPC mice revealed very different messenger RNA (mRNA) and protein profiles. IL17A-/- fibroblasts displayed the ability to restrain tumor cell invasion by producing factors involved in extracellular matrix remodeling, increasing T cell recruitment, and producing higher levels of cytokines and chemokines favoring T helper 1 cell recruitment and activation and lower levels of those recruiting myeloid/granulocytic immune cells. Single-cell quantitative PCR on isolated fibroblasts confirmed a very divergent profile of IL17A-proficient and -deficient cells. All these features can be ascribed to increased levels of IL17F observed in the sera of IL17A-/- mice, and to the higher expression of its cognate receptor (IL17RC) specifically in IL17A-/- cancer-associated fibroblasts (CAFs). In addition to the known effects on neoplastic cell transformation, the IL17 cytokine family uniquely affects fibroblasts, representing a suitable candidate target for combinatorial immune-based therapies in PDA.
Applied Research Center University of Verona 37134 Verona Italy
Department of Diagnostics and Public Health University of Verona 37134 Verona Italy
Department of Immunology University of Toronto Toronto ON M5S 1A8 Canada
Department of Medical Biophysics University of Toronto Toronto ON M5G 1L7 Canada
Department of Medicine University of Hong Kong 999077 Hong Kong
Department of Molecular Biotechnology and Health Sciences University of Torino 10126 Torino Italy
Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA 02115
Faculty of Medicine Charles University Prague 12108 Czech Republic
Faculty of Science Charles University Prague 12800 Czech Republic
Molecular Biotechnology Center University of Torino 10126 Torino Italy
References provided by Crossref.org
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