Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer
Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer
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DOI：
10.1016/j.immuni.2018.11.015
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发表时间：
2019-01-15
期刊：
影响因子：
32.4
通讯作者：
Grivennikov, Sergei, I
中科院分区：
文献类型：
--
作者：
Dmitrieva-Posocco, Oxana;Dzutsev, Amiran;Grivennikov, Sergei, I
慢性炎症驱动结直肠癌（CRC）的进展。白细胞介素（IL）-17A的表达增加与预后不良相关，IL-17 A阻断剂可抑制CRC临床前模型中的肿瘤进展。在这里，我们研究了IL-1信号传导（IL-17通路的关键调节因子）在CRC微环境中不同细胞类型中的影响。上皮细胞中IL-1受体（IL-1 R1）的基因缺失减轻了CRC APC模型中的肿瘤发生，证明了IL-1信号在早期肿瘤种子生长中的细胞自主作用。IL-1 R1的T细胞特异性消融减少了依赖于IL-17和IL-22的肿瘤引起的炎症，从而减少了CRC进展。IL-1的促肿瘤发生作用被其对骨髓细胞，特别是中性粒细胞的作用抵消，其中IL-1 R1消融导致细菌侵入肿瘤，炎症加剧和侵袭性CRC进展。因此，IL-1信号传导激发细胞类型特异性反应，其总体上设定肿瘤微环境的炎症基调并决定疾病进展的倾向。
Chronic inflammation drives the progression of colorectal cancer (CRC). Increased expression of interleukin (IL)-17A is associated with poor prognosis, and IL-17A blockade curbs tumor progression in preclinical models of CRC. Here we examined the impact of IL-1 signaling, a key regulator of the IL-17 pathway, in different cell types within the CRC microenvironment. Genetic deletion of the IL-1 receptor (IL-1R1) in epithelial cells alleviated tumorigenesis in the APC model of CRC, demonstrating a cell-autonomous role for IL-1 signaling in early tumor seed outgrowth. T cell specific ablation of IL-1R1 decreased tumor-elicited inflammation dependent on IL-17 and IL-22, thereby reducing CRC progression. The pro-tumorigenic roles of IL-1 were counteracted by its effects on myeloid cells, particularly neutrophils, where IL-1R1 ablation resulted in bacterial invasion into tumors, heightened inflammation and aggressive CRC progression. Thus, IL-1 signaling elicits cell-type-specific responses, which, in aggregate, set the inflammatory tone of the tumor microenvironment and determine the propensity for disease progression.