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

• 批准号: 10654777
• 负责人: Song Li
• 金额: $ 43.35万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10654777
• 关键词: Acceleration; Affect; Bioinformatics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer Patient; Cell Line; Cell Nucleus; Cells; Combination Drug Therapy; Data; Development; Down-Regulation; Epithelial Cells; Epithelium; Family; Flow Cytometry; Genes; Genetic Transcription; Histologic; Human; Immune; Immune Tolerance; Immune response; Immunologic Surveillance; Immunotherapy; Infection; Infiltration; 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 Promotion; Tumor Suppression; Tumor Suppressor Genes; Tumor Tissue; Work; anti-CTLA4; anti-PD-1; anti-tumor immune response; cancer immunotherapy; cancer survival; cancer therapy; cell mediated immune response; chemotherapy; clinically relevant; constitutive expression; 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; synergism; systemic toxicity; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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 阻断（ICB）疗法。 TME 中缺乏免疫刺激“危险”信号分子可能是一个主要因素 有助于肿瘤免疫治疗的抵抗。因此，通过过度表达来重新编程 TME Alarmin 代表了一种新颖且有前途的肿瘤免疫疗法。我们发现IL-33是一种 “危险”信号在正常肺上皮细胞中表达，但在人类恶性肿瘤中急剧下调 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 的丢失 (TP53) 负责多种人类肿瘤发生过程中上皮细胞中 IL-33 的下调 癌症。此外，与 p53 WT 小鼠肺肿瘤相比，p53 缺陷的 IL-33 表达降低 细胞。这些数据表明IL-33的下调是肿瘤免疫逃避的主要机制。使用 小鼠肿瘤模型中，我们证明 IL-33 在免疫原性小鼠肿瘤细胞中高表达 在ICB肿瘤治疗过程中其水平可能进一步升高。重要的是，我们表明 ST2/IL-33R ICB 疗法的治疗效果需要信号传导。此外，我们还发现肿瘤组织 IL-33 的表达与化疗和 ICB 协同抑制肺肿瘤生长。还有 治疗效果的提高与 CD103+CD8+ T 细胞功能和数量的增加相关 以及 Treg 的减少。我们假设一种基于 TME 重编程的新型免疫疗法 “警报素”IL-33 通过促进肿瘤细胞与化疗和 ICB 免疫治疗产生协同作用 CD103+CD8+T细胞。 SA1。检验以下假设：肿瘤抑制基因 p53 的缺失会导致肿瘤抑制基因下降。 调节上皮 IL-33 表达，导致肺肿瘤的肿瘤免疫监视减少， 加速肺部肿瘤进展。 SA2。我们将专注于开发一种基于 单独或与任一 PD1 mAb 联合共递送 IL-33 表达质粒和紫杉醇 (PTX) 或基于 CTLA-4 mAb 的 ICB。