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)可以极大地延长应答者的生存时间。 然而，ICB应答率的显著提高是当务之急。我们发现IL33是 在肺和皮肤等衬里组织的正常上皮细胞中表达，但在高密度脂蛋白中表达显著下调。 人类多发性癌中肿瘤细胞的分级。这些临床数据支持这样一种观点，即下调 IL33是肿瘤免疫逃逸的主要机制。IL-33在当前ICB治疗中的作用 没有被探索过。有趣的是，我们的生物信息学分析显示，IL33受体ST2mRNA是 PD-1阻断治疗成功后，肿瘤组织中表达上调。使用老鼠模型，我们展示了 提示ICB治疗需要IL33/ST2信号转导途径。此外，我们还演示了 ICB瘤治疗过程中免疫原性小鼠肿瘤细胞高表达IL33及肿瘤表达IL33 对ICB治疗的反应是必需的。尽管有这些强有力的证据支持阿司匹林的抗肿瘤作用 无论是内源性的还是使用的IL33，潜在的分子和细胞机制都不是很好 明白了。我们的初步数据显示，ICB诱导的肿瘤表达的IL33推动了明显的免疫 肿瘤微环境(TME)中的细胞重组。我们进一步证明了其抗肿瘤作用。 IL33依赖于Dc1和CD8T细胞，提示它们在IL33的抗肿瘤作用中起锚定作用。 有趣的是，IL33还导致ST2 Treg细胞在TME中聚集，这可能会抵消抗肿瘤作用 IL33的作用，维持免疫平衡。我们假设肿瘤来源的IL33是反应的基础 通过促进免疫细胞网络的急剧重组来进行ICB肿瘤的免疫治疗 我也是。SA1决定ICB肿瘤治疗诱导肿瘤细胞IL33表达的方式。SA2.我们将定义 IL33如何组织免疫细胞网络，介导对ICB肿瘤治疗的反应。SA3.测定 调节性T细胞(Tregs)中ST2信号如何限制IL33的抗肿瘤活性。

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.