IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D
IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D
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DOI：
10.1158/2326-6066.cir-20-0431
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发表时间：
2021-03-01
影响因子：
10.1
通讯作者：
Laoui, Damya
中科院分区：
文献类型：
--
作者：
Kiss, Mate;Vande Walle, Lieselotte;Laoui, Damya
IL 1 β是炎症的中心介质。IL 1 β的分泌通常需要炎性小体的蛋白水解成熟和gasdermin D（GSDMD）的膜孔形成。新出现的证据表明IL 1 β在促进患者癌症进展中起重要作用，但其潜在机制尚不明确。在这里，我们已经在两种不同的小鼠肿瘤模型中显示了IL 1 β在驱动肿瘤进展中的关键作用。值得注意的是，宿主中炎性体、半胱天冬酶-8以及成孔蛋白GSDMD和混合谱系激酶结构域样蛋白的激活对于肿瘤内生物活性IL 1 β的释放是不确定的。炎性体非依赖性IL 1 β释放促进全身中性粒细胞扩增，并促进肿瘤中T细胞抑制性中性粒细胞的积累。此外，IL 1 β对于抗血管生成治疗引发的中性粒细胞浸润至关重要，从而有助于治疗诱导的免疫抑制。IL 1 β的缺失使得肿瘤内CD 8（+）效应T细胞聚集，随后激活肿瘤相关巨噬细胞。CD 8（+）T细胞或巨噬细胞的耗竭消除了IL 1 β缺陷小鼠中的肿瘤生长抑制，证明了CD 8（+）T细胞-巨噬细胞串扰在抗肿瘤免疫应答中的关键作用。总体而言，这些结果支持IL 1 β通过建立免疫抑制微环境而发挥的促肿瘤作用，并表明炎性小体活化对于肿瘤中该细胞因子的释放不是必需的。
IL1 beta is a central mediator of inflammation. Secretion of IL1 beta typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1 beta in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1 beta in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1 beta. Inflammasome-independent IL1 beta release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1 beta was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1 beta allowed intratumoral accumulation of CD8(+) effectorT cells that subsequently activated tumor-associated macrophages. Depletion of either CD8(+) T cells or macrophages abolished tumor growth inhibition in IL1 beta-deficient mice, demonstrating a crucial role for CD8(+) T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-romoting role for IL1 beta through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.