Environmental respiratory hazards epigenetically reprogram macrophages to support tumor progression in lung cancer in never smokers 4703

Abstract Description In recent decades, the incidence of lung cancer (LC) in never smokers (LCINS) has steadily increased, now the 5th leading cause of cancer mortality, and environmental respiratory hazards (ERHs) are implicated in LCINS etiology. Macrophages (Mφ) pre-condition the lung to support tumor initiation, but how the Mφ response to ERHs effects the pre-malignant microenvironment is unknown. We performed spatial transcriptomics on tumor samples from 156 LC patients, ∼20% never smokers, and 70 paired non-malignant lung tissues. Transcriptional profiles were generated from Mφs and local epithelium enriched or devoid of Mφ infiltrate. Compared to smokers, Mφs in LCINS tumors expressed distinct profiles associated with antigen uptake, degranulation, and IFN signaling. Cancer cells adjacent to Mφ in LCINS tumors upregulated IL-10, TLR, growth factor signaling and tissue remodeling pathways which were absent in Mφ devoid regions. Geospatial modeling of patient ERH exposures correlated with increased LCINS Mφ gene signatures in both tumors and non-malignant lung tissues. Lung Mφs from ERH exposed mice confirmed LCINS expression profiles associated with cancer development and were epigenetically sustained via H3K4me1 and chromatin remodeling and transient ERH exposure established wound-healing Mφs which increased LC burden upon carcinogen challenge. These findings indicate that epigenetic adaptation of Mφs in response to ERHs may contribute to increased LC susceptibility in never smokers. Funding Sources VA Merit Award 01CX00255; Pennsylvania Department of Health; University of Pittsburgh Department of Cardiothoracic Surgery Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)