Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33–activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25–activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R–expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation–driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-γ (IFN-γ)–mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25–ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.

中文翻译：

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先天性 IL-25–ILC2–MDSC 轴为 Apc 突变驱动的肠道肿瘤发生创造了癌症许可的微环境


白介素 25 (IL-25) 和第 2 类先天淋巴细胞 (ILC2) 可以保护宿主免受肠道蠕虫感染，并与不适当的过敏反应相关。先前发现 IL-33 激活的 ILC2 可以增强保护性组织特异性胰腺癌免疫力。在这里，我们证明肠道 IL-25 激活的 ILC2 创建了一个先天的癌症许可微环境。肿瘤较高的结直肠癌（CRC）患者白细胞介素25表达降低了存活率，并增加了表达 IL-25R 的肿瘤驻留 ILC2 和骨髓源性抑制细胞 (MDSC)，这些细胞与抗肿瘤反应受损相关。消除 IL-25 信号可减少肿瘤，使预期寿命几乎翻倍阿普克自发性肠道肿瘤发生的突变驱动模型。从机制上讲，IL-25 促进肿瘤内的 ILC2，从而维持肿瘤浸润的 MDSC，从而抑制抗肿瘤免疫。治疗性抗体介导的 IL-25 信号传导阻断可减少瘤内 ILC2、MDSC 和腺瘤/腺癌，同时增加抗肿瘤适应性 T 细胞和干扰素-γ (IFN-γ) 介导的免疫力。因此，先天上皮源性细胞因子 IL-25 和 IL-33 以及 ILC2 在癌症中的作用不能一概而论。 CRC 中 IL-25-ILC2 轴的促肿瘤性质凸显了该通路作为 CRC 的潜在治疗靶点。