Study of Interleukin 33 as a new immunotherapy of lung cancer

白细胞介素33作为肺癌新型免疫疗法的研究

基本信息

批准号：
10703786
负责人：
Song Li
金额：
$ 26.69万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10703786
关键词：
Affect Bioinformatics CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cancer Patient Cell Nucleus Cells Combination Drug Therapy Data Development Down-Regulation Epithelial Epithelial Cells Family Flow Cytometry Genes Genetic Transcription Histologic Human Immune Immune Tolerance Immune response Immunologic Surveillance Immunotherapy Infection Inflammation Interleukin-1 Interleukins Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Microscopy Modality Modeling Molecular Monoclonal Antibodies Mus Mutate Mutation Paclitaxel Plasmids Regulatory T-Lymphocyte Resistance Role Signal Transduction Signaling Molecule Site Solid Neoplasm TP53 gene Testing Th1 Cells The Cancer Genome Atlas Therapeutic Therapeutic Effect Tissues Transgenic Mice Translations Treatment Efficacy Tumor Escape Tumor Immunity Tumor Suppression Tumor Suppressor Genes Tumor Tissue Work anti-CTLA4 anti-PD-1 anti-tumor immune response base cancer immunotherapy cancer survival cancer therapy cell mediated immune response chemotherapy clinically relevant cytokine cytotoxic gain of function gene delivery system gene therapy genetic approach high dimensionality immune checkpoint blockade immunogenic improved loss of function lung cancer cell lung tumorigenesis member mouse model neoplasm immunotherapy neoplastic cell novel overexpression programmed cell death protein 1 resistance mechanism response systemic toxicity tumor tumor growth tumor microenvironment tumor progression tumorigenesis

Affect Bioinformatics CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cancer Patient Cell Nucleus Cells Combination Drug Therapy Data Development Down-Regulation Epithelial Epithelial Cells Family Flow Cytometry Genes Genetic Transcription Histologic Human Immune Immune Tolerance Immune response Immunologic Surveillance Immunotherapy Infection Inflammation Interleukin-1 Interleukins Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Microscopy Modality Modeling Molecular Monoclonal Antibodies Mus Mutate Mutation Paclitaxel Plasmids Regulatory T-Lymphocyte Resistance Role Signal Transduction Signaling Molecule Site Solid Neoplasm TP53 gene Testing Th1 Cells The Cancer Genome Atlas Therapeutic Therapeutic Effect Tissues Transgenic Mice Translations Treatment Efficacy Tumor Escape Tumor Immunity Tumor Suppression Tumor Suppressor Genes Tumor Tissue Work anti-CTLA4 anti-PD-1 anti-tumor immune response base cancer immunotherapy cancer survival cancer therapy cell mediated immune response chemotherapy clinically relevant cytokine cytotoxic gain of function gene delivery system gene therapy genetic approach high dimensionality immune checkpoint blockade immunogenic improved loss of function lung cancer cell lung tumorigenesis member mouse model neoplasm immunotherapy neoplastic cell novel overexpression programmed cell death protein 1 resistance mechanism response systemic toxicity tumor tumor growth tumor microenvironment tumor progression tumorigenesis

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项目摘要

The immune suppressive tumor microenvironment (TME) has limited the response rate of Immune checkpoint blockade (ICB) therapy. Lack of immune stimulatory “danger” signal molecules in TME can be a major factor contributing to resistance to tumor immunotherapy. Therefore, reprogramming the TME by over-expression of alarmin represents a novel and promising tumor immunotherapy. We have found that IL-33, which is a “danger” signal, is expressed in normal lung epithelial cells but drastically down-regulated in human malignant lung cancer cells. Our bioinformatics analysis of the TCGA data has suggested that loss of tumor protein p53 (TP53) is responsible for IL-33 down-regulation in epithelial cells during tumorigenesis of multiple human cancers. In addition, IL-33 expression was reduced in p53 deficient compared to p53 WT murine lung tumor cells. These data suggest that down-regulation of IL-33 is a major mechanism of tumor immune evasion. Using mouse tumor models, we demonstrated that IL-33 was highly expressed in immunogenic murine tumor cells and its level could be further increased during ICB tumor therapy. Importantly, we showed that the ST2/IL-33R signaling was required for therapeutic effect of ICB therapy. Furthermore, we showed that tumor tissue expression of IL-33 synergized with both chemotherapy and ICB in inhibiting lung tumor growth. And the increased therapeutic efficacy was associated with increases in function and number of CD103+CD8+ T cells as well as decreases in Treg. We hypothesize that a novel immunotherapy based on reprogramming TME by “alarmin” IL-33 synergizes with chemotherapy and ICB immunotherapy through promoting tumoral CD103+CD8+ T cells. SA1. Test the hypothesis that loss of the tumor suppressor gene p53 causes the down- regulation of epithelial IL-33 expression, leading to reduced tumor immune surveillance of lung tumor and accelerated lung tumor progression. SA2. We will focus on development of an improved therapy that is based on codelivery of IL-33 expressing plasmid and paclitaxel (PTX), alone or in combination with either PD1 mAbs or CTLA-4 mAbs-based ICB.

免疫抑制性肿瘤微环境（TME）限制了免疫检查点的反应率块（ICB）治疗。 TME中缺乏免疫刺激器“危险”信号分子可能是一个主要因素有助于抗肿瘤免疫疗法。因此，通过过表达对TME进行重新编程 Alarmin代表一种新颖的肿瘤免疫疗法。我们发现IL-33是 “危险”信号在正常的肺上皮细胞中表达，但在人类恶性肿肺癌细胞。我们对TCGA数据的生物信息学分析表明，肿瘤蛋白p53的丧失（TP53）负责多个人的肿瘤发生期间上皮细胞中的IL-33下调癌症。另外，与p53 wt鼠肺肿瘤相比，p53缺乏率降低了IL-33的表达细胞。这些数据表明，IL-33的下调是肿瘤免疫进化的主要机制。使用小鼠肿瘤模型，我们证明了IL-33在免疫原性鼠肿瘤细胞中高度表达在ICB肿瘤治疗期间，它的水平可以进一步提高。重要的是，我们证明了ST2/IL-33R ICB治疗的治疗作用需要信号传导。此外，我们显示了肿瘤组织 IL-33的表达与化学疗法和ICB抑制肺部肿瘤生长相结合。和提高的治疗效率与CD103+ CD8+ T细胞的功能和数量的增加有关以及Treg的下降。我们假设一种基于重编程TME的新型免疫疗法 “ Alarmin” IL-33通过促进肿瘤协同化疗和ICB免疫疗法协同 CD103+ CD8+ T细胞。 SA1。检验以下假设：肿瘤抑制基因p53的丧失会导致下降调节上皮IL-33表达，导致肺部肿瘤的肿瘤免疫监测降低加速肺部肿瘤进展。 SA2。我们将专注于开发基于改进的疗法关于IL-33表达质粒和紫杉醇（PTX）的代码传递，单独或与任何两种PD1 mAb组合或基于CTLA-4 MABS的ICB。