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

Abstract

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.

Heterogeneity in Pancreatic Cancer Fibroblasts—TGFβ as a Master Regulator?

“…The CAFs from IL-17 deficient tumours exhibited significant gene expression changes including elevated TGFβ signalling components. Fibrosis was enhanced but crucially, the stroma was of a less compact and more immune-permissive nature resulting in increased T cell infiltration and suggesting the use of IL-17 inhibitors as part of combinatorial strategies [ 101 ].…”

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line

“…NFkB provides a mechanistic link between inflammation and cancer [ 26 ], where IL-17 can activate the canonical NFkB signaling pathway [ 27 ], and switches on the pro-tumorigenic program in pancreatic cancers [ 28 ]. Chronic inflammation causes elevated constitutive activity of NFkB with the release of cytokines such as TNFa, IL-1b, IL-6 IL-8 and subsequently STAT3 activation [ 25 ].…”

Modeling pancreatic cancer in mice for experimental therapeutics

“…The KPC mouse model has been further utilized to develop gene specific knockout (KO) models to elucidate their role on PDAC pathobiology. For example, disruption of genes specific to stemness, metabolism, metastasis, glycosylation and immune pathways, have been demonstrated to alter the pathological features of gene specific KPC KO models [207,210,218,219]. Despite several advantages, there is a variability in tumor initiation, progression, and incidences of metastasis in KPC mice, which can impact the experimental readouts during preclinical testing of therapeutic approaches.…”