Chronic Exposure to House Dust Mites: A New Risk Factor for Lung Cancer in Never Smokers

长期接触屋尘螨：从不吸烟者患肺癌的新危险因素

基本信息

批准号：
10737437
负责人：
Samuel P Bertin
金额：
$ 61.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-06 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737437
关键词：
A/J Mouse Acceleration Allergic Reaction Allergic inflammation Antibodies Applications Grants Awareness Biological Markers Cancer Etiology Cancer Model Cancer Patient Carcinogens Cells Chemicals Chronic Cytometry DNA DNA Damage Data Development Diagnosis Dose Environmental Risk Factor Epithelial Cells Etiology Exposure to Genes Genetic Predisposition to Disease Genomic DNA Goals Human Immunofluorescence Immunologic In Vitro Incidence Inflammasome Inflammation Interleukin-1 beta Intervention Investigation KRAS2 gene KRASG12D Link Lung Lung Neoplasms Macrophage Malignant Neoplasms Malignant neoplasm of lung Measures Mus Mutate Mutation Myeloid Cells Organoids Outcome Patients Physiological Plasma Population Predisposition Preventive Production Prognosis Pulmonary Inflammation Pyroglyphidae Research Design Risk Risk Factors Role Signal Pathway Signal Transduction Somatic Mutation Stains Testing Therapeutic Translating Tumor Immunity Tumor Promotion Tumor-Derived Vaccines Work airborne allergen cancer initiation cancer type exposed human population genome sequencing in vivo inhibitor intraperitoneal mouse model neutrophil never smoker novel patient subsets pre-clinical programmed cell death protein 1 recruit single-cell RNA sequencing targeted treatment transcriptome sequencing transcriptomics tumor tumor growth tumor microenvironment whole genome

项目摘要

ABSTRACT The incidence of LC in never-smokers (LCINS) has been increasing but the etiology of this cancer type is largely unknown. We have generated exciting preliminary data showing that exposure to house dust mites (HDM), the most common indoor aeroallergen worldwide, not only provokes allergic reactions and inflammation in the lungs, but also induces pro-tumor inflammation and DNA damage, and accelerates lung cancer (LC) development in three preclinical mouse models of LC at a dose within the range of the annual human HDM exposure. We identified that HDM genomic DNA is present in the tumors of a high percentage of LCINS patients and that it is a strong activator of the AIM2 inflammasome and inducer of IL-1β secretion. Based on these new findings, we hypothesize that long-term exposure to HDM increases the risk of LC development in susceptible hosts (i.e., mice and humans genetically predisposed to LC or co-exposed to other lung carcinogens). Our objectives in this proposal are: 1) to investigate the cellular mechanisms by which chronic HDM exposure changes the lung microenvironment and makes it conducive to LC development, 2) to determine whether HDM has mutagenic effects by studying the mutational signatures potentially linked to HDM exposure in mice in vivo and in human lung organoids in vitro, and 3) to translate these findings to LCINS patients by identifying the composition of the lung tumor microenvironment (TME) and the mutational signature profiles in a subgroup of patients with signs of prior exposure to HDM. Our long-term goal is to increase public awareness of the risk that chronic exposure to HDM may pose for the development of LCINS. Thus, we propose the following three specific aims (SA): in SA- 1, we will test whether HDM exposure changes the cellular composition of the lung TME, in SA-2, we will determine whether HDM exposure induces somatic mutations in lung epithelial cells, and in SA-3, we will evaluate whether HDM exposure can be used as a biomarker for diagnosis, prognosis, and targeted therapy in LCINS patients. The expected outcomes of this work are 1) to identify the cellular mechanisms by which HDM exposure promotes LC development in susceptible hosts, 2) to demonstrate that chronic exposure to HDM is a new environmental risk factor for LCINS, 3) to provide strong scientific support for the development of novel preventive (e.g., HDM avoidance) and therapeutic (e.g., anti-HDM vaccine, anti-IL-1β antibodies, and NLRP3/AIM2 inhibitors) interventions in LCINS patients chronically exposed to HDM, and 4) to expand the investigations of exposure to other aeroallergens as potential risk factors in LC.

抽象的从不吸烟者 (LCINS) 中 LC 的发病率一直在增加，但这种癌症类型的病因很大程度上是我们已经生成了令人兴奋的初步数据，表明接触屋尘螨（HDM）是最危险的。全世界最常见的室内空气过敏原，不仅会引起过敏反应和肺部炎症，还会诱发促肿瘤炎症和 DNA 损伤，并加速肺癌 (LC) 的发展三个临床前小鼠模型的 LC 剂量在人类每年 HDM 暴露范围内。确定 HDM 基因组 DNA 存在于高比例 LCINS 患者的肿瘤中，并且 AIM2 炎症小体的强激活剂和 IL-1β 分泌的诱导剂基于这些新发现，我们长期接触 HDM 会增加易感宿主（即，小鼠和人类在遗传上易患肺癌或同时接触其他肺癌致癌物）。建议是： 1) 研究慢性 HDM 暴露改变肺部的细胞机制微环境，使其有利于LC的发展，2）确定HDM是否具有致突变性通过研究小鼠体内和人类体内与 HDM 暴露可能相关的突变特征来确定影响体外肺类器官，3) 通过鉴定肺类器官的组成，将这些发现转化为 LCINS 患者肺肿瘤微环境（TME）和具有以下症状的患者亚组的突变特征谱：我们的长期目标是提高公众对长期接触 HDM 的风险的认识。 HDM 可能会促进 LCINS 的发展，因此，我们提出以下三个具体目标（SA）： 1，我们将测试HDM暴露是否改变肺TME的细胞组成，在SA-2中，我们将确定 HDM 暴露是否会诱导肺上皮细胞的体细胞突变，在 SA-3 中，我们将评估 HDM 暴露是否可以作为诊断、预后和靶向治疗的生物标志物 LCINS 患者这项工作的预期结果是 1) 确定 HDM 的细胞机制。暴露促进易感宿主的 LC 发展，2) 证明长期暴露于 HDM 是一种为LCINS新的环境风险因素，3）为新药的研发提供强有力的科学支撑预防性（例如，避免 HDM）和治疗性（例如，抗 HDM 疫苗、抗 IL-1β 抗体和 NLRP3/AIM2 抑制剂）对长期暴露于 HDM 的 LCINS 患者进行干预，4）扩大对接触其他空气过敏原作为 LC 潜在危险因素的调查。