Study of Interleukin 33 as a new immunotherapy of lung cancer

免疫抑制性肿瘤微环境（TME）限制了免疫检查点的应答率 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 导致对肿瘤免疫疗法的抗性。因此，通过过表达TME来重编程TME， Alarmin代表了一种新的和有前途的肿瘤免疫疗法。我们已经发现IL-33，这是一种 “危险”信号，在正常肺上皮细胞中表达，但在人类恶性肿瘤中表达显著下调。 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的缺失 在多种人类肿瘤的发生过程中，TP 53负责上皮细胞中IL-33的下调。 癌的此外，与p53 WT小鼠肺肿瘤相比，p53缺陷小鼠肺肿瘤中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 在小鼠肿瘤模型中，我们证明IL-33在免疫原性小鼠肿瘤细胞中高度表达 在ICB肿瘤治疗过程中其水平可进一步升高。重要的是，我们发现ST 2/IL-33 R 信号传导是ICB疗法的治疗效果所必需的。此外，我们发现肿瘤组织 IL-33的表达与化疗和ICB两者协同抑制肺肿瘤生长。和 治疗效果的增加与CD 103 + CD 8 + T细胞的功能和数量的增加有关 以及Treg的减少。我们假设，一种新的免疫疗法的基础上重新编程TME， “alarmin”IL-33通过促进肿瘤生长与化疗和ICB免疫疗法协同作用 CD 103 + CD 8 + T细胞。SA 1.检验肿瘤抑制基因p53的缺失导致肿瘤细胞减少的假设- 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。SA 2.我们将专注于开发一种基于 IL-33表达质粒和紫杉醇（PTX）单独或与PD 1 mAb联合共递送时 或基于CTLA-4 mAb的ICB。

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.