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

• 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
• 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

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.

摘要 不吸烟者中LC（LCINS）的发病率一直在增加，但这种癌症类型的病因主要是 未知我们已经产生了令人兴奋的初步数据，显示暴露于屋尘螨（HDM）， 全世界最常见的室内空气过敏原，不仅引起肺部的过敏反应和炎症， 但也诱导促肿瘤炎症和DNA损伤，并加速肺癌（LC）的发展， 三种LC临床前小鼠模型，剂量在人类HDM年暴露量范围内。我们 确定HDM基因组DNA存在于高百分比的LCINS患者的肿瘤中， AIM 2炎性体的强激活剂和IL-1β分泌的诱导剂。基于这些新发现，我们 假设长期暴露于HDM增加了易感宿主中LC发展的风险（即， 遗传上易患LC或共同暴露于其它肺致癌物的小鼠和人）。我们在这方面的目标 建议：1）研究慢性HDM暴露改变肺的细胞机制 微环境，使其有利于LC的发展，2）确定HDM是否具有致突变性 通过研究可能与小鼠体内和人体HDM暴露相关的突变特征， 体外肺类器官，和3）通过鉴定LCINS患者的组成，将这些发现转化为LCINS患者。 肺肿瘤微环境（TME）和突变特征谱在一个亚组的迹象， 之前接触过HDM。我们的长期目标是提高公众对长期暴露于 HDM可能对LCINS的发展提出了建议。因此，我们提出以下三个具体目标（SA）：在SA- 在SA-1中，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暴露是否可用作诊断、预后和靶向治疗的生物标志物， LCINS患者。这项工作的预期成果是：1）确定HDM的细胞机制， 暴露促进易感宿主LC的发展，2）证明长期暴露于HDM是一种 为LCINS新的环境风险因子，3）为开发新的LCINS提供强有力的科学支持 预防性的（例如，HDM避免）和治疗（例如，抗HDM疫苗、抗IL-1β抗体，以及 NLRP 3/AIM 2抑制剂）干预LCINS患者长期暴露于HDM，和4）扩大 研究暴露于其他空气过敏原作为LC的潜在风险因素。