Study of Interleukin 33 as a new immunotherapy of lung cancer

免疫抑制肿瘤微环境限制了免疫检查点的反应速度 阻断(ICB)疗法。TME中缺乏免疫刺激的“危险”信号分子可能是一个主要因素 对肿瘤免疫治疗产生抵抗力。因此，通过过度表达TME来重新编程TME ALARMIN代表了一种新的、有前途的肿瘤免疫治疗方法。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的丢失 (TP53)是多种人肿瘤发生过程中上皮细胞IL-33下调的相关基因 癌症。此外，与P53基因缺陷的小鼠肺癌相比，P53基因缺陷的小鼠肺肿瘤中IL-33的表达降低 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。vbl.使用 小鼠肿瘤模型，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，我们证明了ST2/IL-33R ICB治疗的疗效需要信号转导。此外，我们发现肿瘤组织 IL-33的表达与化疗和ICB协同抑制肺癌生长。以及 治疗效果的提高与CD103 CD8 T细胞的功能和数量的增加有关 以及Treg的减少。我们推测，一种新的基于TME重新编程的免疫疗法 IL-33通过促进肿瘤与化疗和ICB免疫治疗的协同作用 CD103 CD8 T细胞。SA1.验证肿瘤抑制基因P53缺失导致基因下调的假设。 调节上皮细胞IL-33的表达，导致肺癌和肺癌的肿瘤免疫监视减少 加速了肺癌的发展。SA2.我们将专注于开发一种改进的疗法，这是基于 IL-33表达载体与紫杉醇(PTX)单独或与PD1单抗联合传递的研究 或以CTLA-4单抗为基础的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.