IL-17RA信号在晚期结直肠癌发生过程中提供双重肿瘤抑制功能

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-02-28 DOI:10.1016/j.immuni.2025.02.005

Dominic Denk, Mallika Ramakrishnan, Claire Conche, Charles Pallangyo, Marina Pesic, Fatih Ceteci, Kilian B. Kennel, Asude C. Kirisözü, Esther Engel, Kathleen Mohs, Birgit Ritter, Angeles Macias Pardo, Ezgi Özkurt, Falk Hildebrand, Ari Waisman, Melek C. Arkan, Florian R. Greten

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引用次数: 0

摘要

白细胞介素(IL)-17家族细胞因子的表达与促肿瘤炎症有关。我们发现IL17RA的低表达与晚期结直肠癌（CRC）患者较差的预后相关。在小鼠CRC模型中，肠上皮细胞（IECs）中Il17ra的缺失通过增加表皮生长因子受体的表达和随后的激酶Src的激活，增强了上皮到间充质转化（EMT）。然而，这些小鼠被保护免受转移性疾病；Il17ra缺失会损害肠道屏障功能，增强全身真菌入侵和相关免疫。然而，在巨噬细胞中，IL-17RA需要在真菌诱导的dectin-1结合时激活脾脏酪氨酸激酶（Syk）， IL-17RA消融会损害IL-18的释放和保护性CD8+ T细胞介导的抗肿瘤免疫。在微卫星稳定型（MSS）结直肠癌模型中，联合重组IL-17和热杀伤白色念珠菌使结直肠肿瘤对α-PD-1敏感。因此，IL-17RA在结直肠癌中参与两种不同的肿瘤抑制机制，将肿瘤进展过程中的EMT和真菌诱导的抗肿瘤免疫联系起来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis

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IL-17RA signaling provides dual tumor-suppressor function during late-stage colorectal carcinogenesis

Expression of interleukin (IL)-17 family cytokines is associated with tumor-promoting inflammation. We found that low expression of IL17RA associated with worse prognosis in late-stage colorectal cancer (CRC) patients. Deletion of Il17ra in intestinal epithelial cells (IECs) in a murine model of CRC enhanced epithelial-to-mesenchymal transition (EMT) via increased expression of the epidermal growth factor receptor and subsequent activation of the kinase Src. Yet, these mice were protected from metastatic disease; Il17ra deletion impaired intestinal barrier function and enhanced systemic fungal invasion and associated immunity. However, in macrophages, IL-17RA was required for spleen tyrosine kinase (Syk) activation upon fungal-induced dectin-1 engagement, and Il17ra ablation impaired IL-18 release and protective CD8⁺ T cell-mediated anti-tumor immunity. Combining recombinant IL-17 and heat-killed Candida albicans rendered colorectal tumors sensitive to α-PD-1 treatment in a model of microsatellite stable (MSS) CRC. Thus, IL-17RA engages two distinct tumor-suppressive mechanisms in CRC, linking EMT and fungal-induced anti-tumor immunity during tumor progression.

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.