Study of the IL-33-driven immune cell organization underpinning responses to immune checkpoint blockade cancer therapy

免疫检查点阻断癌症治疗（ICB）可以大大延长应答者的生存期。 然而，迫切需要大大提高国际竞争性银行的答复率。我们已经发现IL 33是 在肺和皮肤等衬里组织的正常上皮细胞中表达，但在高表达的上皮细胞中显著下调。 在多种人类癌症中分级肿瘤细胞。这些临床数据支持了这样一种观点，即， IL 33是肿瘤免疫逃避的主要机制。IL-33如何促进对当前ICB治疗的反应 没有被探索。有趣的是，我们的生物信息学分析显示，IL 33受体ST 2 mRNA是 在成功的PD-1阻断治疗后在人肿瘤组织中上调。使用小鼠模型， IL 33/ST 2信号通路是ICB治疗效果所必需的。此外，我们还证明， 在ICB肿瘤治疗期间，IL 33在免疫原性鼠肿瘤细胞中高度诱导，并且肿瘤表达的IL 33 对ICB治疗的反应需要。尽管这些强有力的证据支持抗肿瘤功能， 无论是内源性的还是给药的IL 33，其潜在的分子和细胞机制都不是很清楚。 明白我们的初步数据表明，ICB诱导的肿瘤表达的IL 33驱动了显著的免疫应答。 肿瘤微环境（TME）中的细胞重组。我们进一步证明， IL 33依赖于DC 1和CD 8 + T细胞，表明它们在锚定IL 33的抗肿瘤作用中的作用。 有趣的是，IL 33还导致TME中ST 2 + Treg细胞的积累，这可能抵消TME中的抗肿瘤活性。 IL-33的作用，维持免疫平衡。我们假设肿瘤来源的IL 33支持应答， ICB肿瘤免疫治疗，通过促进免疫细胞网络的急剧重组， TME。SA 1确定ICB肿瘤治疗如何在肿瘤细胞中诱导IL 33表达。SA 2.我们将定义 IL 33如何组织介导对ICB肿瘤治疗反应的免疫细胞网络。SA 3.确定 调节性T细胞（Tcells）中的ST 2信号传导如何限制IL 33的抗肿瘤活性的机制。

The immune checkpoint blockade cancer therapy (ICB) can greatly prolong survival in responders. However, significant improvement of the response rate of ICB is in urgent need. We have found that IL33 is expressed in normal epithelial cells of lining tissues such as lung and skin but drastically down-regulated in high- grade tumor cells in multiple human carcinomas. These clinical data support the notion that down-regulation of IL33 is a major mechanism of tumor immune evasion. How IL-33 contributes to responses to current ICB therapy is not explored. Interestingly, our bioinformatics analysis revealed that the IL33 receptor ST2 mRNA is upregulated in human tumor tissues after successful PD-1 blockade treatment. Using mouse models, we showed that the IL33/ST2 signaling was required for therapeutic effect of ICB therapy. In addition, we demonstrated that IL33 was highly induced in immunogenic murine tumor cells during ICB tumor therapy and tumor-expressed IL33 was required for responses to ICB therapy. Despite these strong evidence supporting an antitumor function of both endogenous and administered IL33, the underlying molecular and cellular mechanisms are not well understood. Our preliminary data showed that ICB-induced tumor-expressed IL33 drove conspicuous immune cell re-organization in the tumor microenvironment (TME). We further demonstrated that the antitumor effect of IL33 is dependent on DC1 and CD8+ T cells, suggesting their role in anchoring the antitumor effect of IL33. Interestingly, IL33 also led to accumulation of ST2+ Treg cells in the TME, which might counteract the antitumor effect of IL33 and maintain an immune equilibrium. We hypothesize that tumor-derived IL33 underpins responses to ICB tumor immunotherapy through promoting a drastic reorganization of the immune cellular network in the TME. SA1 Determine how IL33 expression is induced in tumor cells by ICB tumor therapy. SA2. We will define how IL33 organizes the immune cellular network that mediates responses to ICB tumor therapy. SA3. Determine the mechanisms how ST2 signaling in regulatory T cells (Tregs) limits antitumor activities of IL33.