胰腺上皮细胞IL-17/IL-17RA信号驱动B7-H4的表达,从而促进肿瘤发生。

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Susana Castro-Pando, Rian M Howell, Le Li, Marilina Mascaro, Erika Y Faraoni, Olivereen Le Roux, David Romanin, Virginia Tahan, Erick Riquelme, Yu Zhang, Jay K Kolls, James P Allison, Guillermina Lozano, Seyed J Moghaddam, Florencia McAllister
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引用次数: 0

摘要

遗传学和药理学方法表明,IL-17 是胰腺癌发生和发展的必要条件,尤其是在炎症背景下。IL-17 介导的胰腺肿瘤发生的细胞区系和下游分子介质尚未完全确定。我们在胚胎激活或诱导 Kras 的背景下,通过产生白细胞介素 17 受体 A(IL-17RA)基因被从胰腺上皮细胞区系中删除的转基因动物,以及通过产生 IL-17RA 缺失(IL17-RA-/-)骨髓嵌合体的造血细胞区系,对所需的细胞区系进行了研究。在胰腺上皮细胞中缺失IL-17RA,而在造血细胞中缺失IL-17RA,会导致恶性肿瘤前期病变的发生和发展延迟,并增加CD8+细胞毒性T细胞对肿瘤微环境的浸润。胰腺区系中缺少IL-17RA会影响上皮细胞的转录谱,从而调节干性和免疫途径。有趣的是,由Vtcn1基因编码的已知T细胞活化抑制剂B7-H4是胰腺肿瘤发生早期通过IL17上调最多的检查点分子,其基因缺失可延缓胰腺恶性肿瘤前病变的发展并减少免疫抑制。我们揭示了胰腺上皮IL-17RA对胰腺肿瘤发生的要求,它通过重编程胰腺免疫格局来实现,而胰腺免疫格局部分是由B7-H4调控的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis.

IL17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. However, the cellular compartment and downstream molecular mediators of IL17-mediated pancreatic tumorigenesis have not been fully identified. This study examined the cellular compartment required by generating transgenic animals with IL17 receptor A (IL17RA), which was genetically deleted from either the pancreatic epithelial compartment or the hematopoietic compartment via generation of IL17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL17RA from the pancreatic epithelial compartment, but not from hematopoietic compartment, resulted in delayed initiation and progression of premalignant lesions and increased infiltration of CD8+ cytotoxic T cells to the tumor microenvironment. Absence of IL17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness, and immunological pathways. B7-H4, a known inhibitor of T-cell activation encoded by the gene Vtcn1, was the checkpoint molecule most upregulated via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed the development of pancreatic premalignant lesions and reduced immunosuppression. Thus, our data reveal that pancreatic epithelial IL17RA promotes pancreatic tumorigenesis by reprogramming the immune pancreatic landscape, which is partially orchestrated by regulation of B7-H4. Our findings provide the foundation of the mechanisms triggered by IL17 to mediate pancreatic tumorigenesis and reveal the avenues for early pancreatic cancer immune interception. See related Spotlight by Lee and Pasca di Magliano, p. 1130.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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