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疗法（ICB）可以大大延长应答者的生存期。然而，迫切需要显着提高 ICB 的响应率。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，但在高浓度组织中急剧下调对多种人类癌症中的肿瘤细胞进行分级。这些临床数据支持这样的观点：下调 IL33是肿瘤免疫逃避的主要机制。 IL-33 如何促进当前 ICB 疗法的反应没有被探索。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 阻断治疗后，人类肿瘤组织中的表达上调。使用小鼠模型，我们展示了 IL33/ST2信号传导对于ICB疗法的治疗效果是必需的。此外，我们还证明了在 ICB 肿瘤治疗期间，IL33 在免疫原性小鼠肿瘤细胞中被高度诱导，并且肿瘤表达 IL33 是对 ICB 治疗有反应所必需的。尽管有这些强有力的证据支持抗肿瘤功能无论是内源性的还是施用的IL33，其潜在的分子和细胞机制尚不明确明白了。我们的初步数据表明，ICB 诱导的肿瘤表达的 IL33 驱动了显着的免疫肿瘤微环境（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 CD8+ T 细胞，表明它们在锚定 IL33 抗肿瘤作用中的作用。有趣的是，IL33 还导致 TME 中 ST2+ Treg 细胞的积累，这可能会抵消抗肿瘤作用 IL33的作用并维持免疫平衡。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彻底重组来进行 ICB 肿瘤免疫治疗 TME。 SA1 确定 ICB 肿瘤治疗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 ICB 肿瘤治疗反应的免疫细胞网络。 SA3。决定调节性 T 细胞 (Treg) 中的 ST2 信号传导如何限制 IL33 的抗肿瘤活性的机制。