Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Cancer Immunol Res. 2018 Apr;6(4):409-421. doi: 10.1158/2326-6066.CIR-17-0218. Epub 2018 Feb 20.
Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa. Although IL33 can prevent colon cancer associated with inflammatory colitis, the contribution of IL33 signaling to sporadic colon cancer remains unknown. Here, we utilized a mouse model of sporadic colon cancer to investigate the contribution of IL33 signaling to tumorigenesis in the absence of preexisting inflammation. We demonstrated that genetic ablation of St2 enhanced colon tumor development. Conversely, administration of recombinant IL33 reduced growth of colon cancer cell allografts. In reciprocal bone marrow chimeras, the concurrent loss of IL33 signaling within radioresistant nonhematopoietic, and the radiosensitive hematopoietic, compartments was associated with increased tumor burden. We detected St2 expression within the radioresistant mesenchymal cell compartment of the colon whose stimulation with IL33 induced expression of NF-κB target genes. Mechanistically, we discovered that St2 deficiency within the nonhematopoietic compartment coincided with increased abundance of regulatory T cells and suppression of an IFNγ gene expression signature, whereas IL33 administration triggered IFNγ expression by tumor allograft-infiltrating T cells. The decrease of this IFNγ gene expression signature was associated with more aggressive disease in human colon cancer patients, suggesting that lack of IL33 signaling impaired the generation of a potent IFNγ-mediated antitumor immune response. Collectively, our data reveal that IL33 functions as a tumor suppressor in sporadic colon cancer. .
白细胞介素 33（IL33）是一种在细胞坏死性死亡时释放的炎症细胞因子。肠道的上皮细胞和基质大量表达 IL33 和其受体 St2。因此，在肠道黏膜的稳态更新过程中，IL33 持续释放。虽然 IL33 可以预防与炎症性结肠炎相关的结肠癌，但 IL33 信号对散发性结肠癌的贡献仍不清楚。在这里，我们利用散发性结肠癌的小鼠模型，在不存在先前存在的炎症的情况下，研究了 IL33 信号对肿瘤发生的贡献。我们证明了 St2 的基因缺失增强了结肠肿瘤的发展。相反，重组 IL33 的给药减少了结肠癌细胞同种异体移植物的生长。在互惠性骨髓嵌合体中，放射抗性非造血细胞和放射敏感造血细胞内同时丧失 IL33 信号与肿瘤负担增加有关。我们在结肠的放射抗性间质细胞区室中检测到 St2 的表达，IL33 刺激该区室诱导 NF-κB 靶基因的表达。从机制上讲，我们发现非造血区室中 St2 的缺乏伴随着调节性 T 细胞的丰度增加和 IFNγ 基因表达谱的抑制，而 IL33 的给药触发了肿瘤同种异体移植物浸润 T 细胞中的 IFNγ 表达。这种 IFNγ 基因表达谱的减少与人类结肠癌患者更具侵袭性的疾病相关，这表明缺乏 IL33 信号会损害强大的 IFNγ 介导的抗肿瘤免疫反应的产生。总的来说，我们的数据表明 IL33 在散发性结肠癌中作为肿瘤抑制因子发挥作用。
