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

摘要 非吸烟者中LC的发病率一直在增加，但这种癌症的病因在很大程度上是 未知。我们已经产生了令人兴奋的初步数据，表明暴露在屋尘螨(HDM)中， 全球最常见的室内空气变应原，不仅会引起肺部过敏反应和炎症， 但也会诱导肿瘤前炎症和DNA损伤，并加速肺癌(LC)的发展 三种临床前LC小鼠模型，剂量在人类HDM年暴露范围内。我们 证实HDM基因组DNA存在于高比例的LCINS患者的肿瘤中，并且它是 是AIM2炎症体的强大激活剂和IL-1β分泌的诱导者。基于这些新发现，我们 假设长期暴露于HDM会增加易感宿主发展为LC的风险(即， 小鼠和人类在遗传上易患上LC或共同暴露于其他肺癌致癌物)。我们在这方面的目标 建议是：1)研究慢性HDM暴露改变肺部的细胞机制 2)判断HDM是否具有致突变性 研究可能与HDM暴露相关的突变特征对小鼠和人类的影响 3)将这些发现转化为LCINS患者，通过鉴定肺组织的组成 肺肿瘤微环境(TME)和突变特征特征在一组有肺癌症状的患者中的分布 以前接触过HDM。我们的长期目标是提高公众对长期接触的风险的认识。 HDM可能对LC-INS的发展起到促进作用。因此，我们提出以下三个具体目标(SA)：在SA中- 1，我们将测试HDM暴露是否改变了肺TME的细胞成分，在SA-2中，我们将 确定接触HDM是否会诱导肺上皮细胞发生体细胞突变，在SA-3中，我们将 评价HDM暴露能否作为诊断、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 新的环境风险因素，3)为新型燃料电池的开发提供强有力的科学支持 预防(如避免患上糖尿病)和治疗性(如抗糖尿病疫苗、抗IL-1β抗体)和 NLRP3/AIM2抑制剂)对慢性暴露于HDM的LCINS患者进行干预，以及4)扩大 暴露于其他空气变应原作为LC潜在危险因素的调查。

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.