Pulmonary macrophages transcriptionally remodel lung epithelium to increase lung cancer susceptibility in response to environmental respiratory hazards in female never smokers 3790

Abstract Description For decades there has been an alarming increase in lung cancer in never smoker (LCINS) that occurs more frequently in young women. Pulmonary macrophages (pMac) play a key role in lung cancer (LC) development and are heavily influenced by sex chromosomes and gonadal hormones. We hypothesize that the pMac response to environmental respiratory hazards (ERHs) is sex-specific and results in divergent immunopathology and susceptibility to LCINS. Using EPA and satellite data, we compared modeled particulate matter ≤2.5µm (PM2.5) exposure levels in 2,944 at-risk patients. Women with high PM2.5 exposures had twice the risk of developing LC compared to men. Spatial transcriptomics was performed on tumors from 15 female and 5 male LCINS patients. Female pMacs expressed pathways promoting tissue remodeling, growth factor signaling, and catabolic metabolism compared to male pMacs which regulated interferon signaling, ROS production, and antigen processing-cross presentation. Compared to males, female FVB/N mice exposed to aerosolized ERHs for 4wks amassed pMacs in the lung. Female pMacs were epigenetically poised to promote cancer development driven by IL-4/IL-33/IgG responses. Notably, pre-exposure to ERHs accelerated carcinogen-induced LC in mice irrespective of sex. These findings suggest sex-based pMac response is involved in LC susceptibility, differences in cancer behavior and outcomes in women with LCINS. Funding Sources Pennsylvania Department of Heath (PI Soloff) Veteran’s Health Administration (I01 CX002558)(PI Soloff) Department of Cardiothoracic Surgery, University of Pittsburgh (PI Soloff) Topic Categories Immune Mechanisms of Human Disease (HUM)