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

IL-33 驱动的免疫细胞组织支持免疫检查点阻断癌症治疗反应的研究

基本信息

批准号：
10431979
负责人：
Binfeng Lu
金额：
$ 13.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-16 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431979
关键词：
Address Bioinformatics CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Carcinoma Cell Nucleus Cells Clinical Clinical Data Combined Modality Therapy Data Down-Regulation Epithelial Cells Equilibrium Family Genomics Human IL6 gene Immune Immune checkpoint inhibitor Immunosuppression In Vitro Infection Interleukin-1 Interleukin-13 Interleukins Link Lung Mediating Messenger RNA Modeling Molecular Mus PD-1 blockade Pattern Play Regulation Regulatory T-Lymphocyte Role Signal Transduction Skin Solid Neoplasm T-Lymphocyte Testing Therapeutic Effect Thinness Tissues Treatment Efficacy Tumor Cell Line Tumor Escape Tumor Tissue Tumor-Derived anti-tumor immune response antitumor effect base cancer immunotherapy cancer therapy cytokine design exhaustion immune checkpoint blockade immunogenic improved in vivo interleukin-21 interleukin-21 receptor member mouse model neoplasm immunotherapy neoplastic cell novel prevent programmed cell death protein 1 receptor response tool tumor tumor growth tumor microenvironment

项目摘要

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.

免疫检查点阻断癌症治疗（ICB）可以大大延长响应者的生存。但是，迫切需要的ICB响应率的显着提高。我们发现IL33是在肺部组织的正常上皮细胞中表达，例如肺和皮肤，但在高 - 多个人类癌中的等级肿瘤细胞。这些临床数据支持下调的观念 IL33是肿瘤免疫逃避的主要机制。 IL-33如何有助于对当前ICB治疗的反应没有探索。有趣的是，我们的生物信息学分析表明，IL33受体ST2 mRNA是成功的PD-1封锁治疗后，在人类肿瘤组织中上调。使用鼠标模型，我们显示了 IL33/ST2信号是ICB治疗的治疗作用所必需的。此外，我们证明了 IL33在ICB肿瘤治疗和肿瘤表达的IL33期间高度诱导了免疫原性鼠肿瘤细胞是对ICB治疗的反应所必需的。尽管这些有力的证据支持了抗肿瘤功能内源性和施用的IL33，潜在的分子和细胞机制都不好理解。我们的初步数据表明，ICB诱导的肿瘤表达的IL33驱动了明显的免疫肿瘤微环境（TME）中的细胞重组。我们进一步证明了抗肿瘤的作用 IL33取决于DC1和CD8+ T细胞，这表明它们在锚定IL33的抗肿瘤作用中的作用。有趣的是，IL33还导致TME中的ST2+ Treg细胞积累，这可能抵消抗肿瘤 IL33的影响并保持免疫平衡。我们假设肿瘤衍生的IL33基础反应通过促进对免疫细胞网络的急剧重组来进行ICB肿瘤免疫疗法 TME。 SA1通过ICB肿瘤治疗确定如何在肿瘤细胞中诱导IL33表达。 SA2。我们将定义 IL33如何组织介导对ICB肿瘤治疗的反应的免疫细胞网络。 SA3。决定该机制是调节T细胞中的ST2信号传导如何限制IL33的抗肿瘤活性。