| First Author | Mucciolo G | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 6 | PubMed ID | 33526692 |
| Mgi Jnum | J:301987 | Mgi Id | MGI:6507107 |
| Doi | 10.1073/pnas.2020395118 | Citation | Mucciolo G, et al. (2021) IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions. Proc Natl Acad Sci U S A 118(6):e2020395118 |
| abstractText | 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. |
