IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions

Abstract

Significance There are controversial data about the protumoral role of pancreatic cancer stroma, and dissecting multiple aspects will help to develop effective tailored therapies. Interleukin-17A (IL17A) has been reported to accelerate pancreatic acinar–ductal metaplasia, be important for maintaining stem-like cancer cells, and recruit immunosuppressive granulocytes into the tumor. Here we unveil a relationship between IL17A and pancreatic stromal cells, which strongly modifies their gene and protein expression profiles. Ablation of IL17A, in fact, modifies the cytokines/factors released by tumor fibroblasts by limiting T cell immunosuppression. IL17A inhibition may represent an important tool for designing novel combined therapeutic approaches. 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.