Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Città della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy.
Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Proc Natl Acad Sci U S A. 2021 Feb 9;118(6). doi: 10.1073/pnas.2020395118.
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.
癌症的一个标志，包括胰腺导管腺癌（PDA），是大量的基质和炎症反应。许多努力已经被用于确定细胞因子和基质中的免疫亚群的抗或促肿瘤作用。在这里，我们研究了白细胞介素 17A（IL17A）的作用及其对肿瘤成纤维细胞和肿瘤微环境的影响。我们使用自发的 PDA 小鼠模型（KPC）与 IL17A 敲除小鼠杂交，显示出广泛的促结缔组织反应，而不会损害免疫浸润。巨噬细胞，特别是 CD80 和 T 细胞，在更早的时间点更为丰富。在 T 细胞中，在 KPC/IL17A 小鼠中观察到 FoxP3 细胞减少和 CD8 T 细胞增加。从 IL17A 和 IL17A KPC 小鼠分离的成纤维细胞显示出非常不同的信使 RNA（mRNA）和蛋白质谱。IL17A 成纤维细胞通过产生参与细胞外基质重塑的因子、增加 T 细胞募集以及产生更高水平有利于 T 辅助 1 细胞募集和激活的细胞因子和趋化因子，同时产生更低水平募集髓样/粒细胞免疫细胞的因子，从而具有抑制肿瘤细胞侵袭的能力。对分离的成纤维细胞进行单细胞定量 PCR 证实了 IL17A 阳性和阴性细胞的非常不同的特征。所有这些特征都可以归因于在 IL17A 小鼠血清中观察到的 IL17F 水平的增加，以及其同源受体（IL17RC）在 IL17A 癌症相关成纤维细胞（CAFs）中的特异性高表达。除了对肿瘤细胞转化的已知影响外，IL17 细胞因子家族还独特地影响成纤维细胞，是 PDA 中组合免疫治疗的合适候选靶标。
