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