Air Pollution Promotes Oncogenic Expansion of Mutant Lung Progenitor Cells

Environmental exposure to substances such as air pollution has been associated with the risk of developing lung cancer, as the fine particulate matter (PM) that comprises air pollution can travel deep within airways and impact lung function. However, the mechanisms by which exposure to PM promotes lung cancer formation remain unknown. To explore the association between air pollution and cancer risk, Hill, Lim, Weeden, and colleagues analyzed the relationship between environmental levels of PM measuring less than or equal to 2.5 μm in diameter (PM_2.5) and the estimated incidence of EGFR-driven lung cancer, which is more common in patients who have little to no history of smoking, and revealed a positive correlation in multiple cohorts from countries with varying ethnicities and ranges of pollution. Notably, assessment of cumulative exposure suggested that 3 years of exposure to high levels of PM_2.5 was sufficient to increase the risk of EGFR-driven lung cancer. To test these findings in vivo, genetically engineered mice were exposed to PM or phosphate-buffered saline for 3 weeks following the induction of oncogenic EGFR^L858R expression in the lungs, demonstrating that PM increased both the number of preinvasive neoplasias and the degree of clonal expansion within lesions. RNA sequencing analysis of lung epithelial cells from PM-treated mice expressing EGFR^L858R indicated the upregulation of inflammatory pathways and genes involved in macrophage recruitment, consistent with the observed increase in CD11b⁺ CD68⁺ interstitial macrophages within the lungs after PM exposure. Moreover, PM exposure reprogrammed alveolar type II cells within the lung epithelium toward a lung progenitor cell state, and this shift in progenitor function was mediated by macrophage secretion of inflammatory cytokines such as interleukin-1β (IL1β) in response to PM. Concomitant administration of an anti-IL1β antibody during PM exposure was sufficient to prevent the development of PM-induced tumors. Together, these findings suggest that air pollution can promote lung cancer through the macrophage-mediated expansion of lung progenitor cells that harbor preexisting driver mutations and highlight the importance of environmental initiatives.

Hill W, Lim EL, Weeden CE, Lee C, Augustine M, Chen K, et al. Lung adenocarcinoma promotion by air pollutants. Nature 2023;616:159–167.

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