Increasing exposure to 2.5 µm particulate matter (PM2.5) increases the risk of non-small cell lung cancer in non-smoking individuals with EGFR mutations. This effect is driven by an influx of macrophages and an increase in the inflammatory mediator IL-1β, which promotes carcinogenesis in airway cells, a study from the University College London showed.


Although smoking is the most important cause of lung cancer, non-smokers can also develop this disease. Evidence exists to link air pollution exposure with lung cancer incidence and mortality [1,2]. However, the molecular mechanism underlying the link between air pollution and lung cancer in non-smokers has not been elucidated. Dr. Charles Swanton (University College London, UK) presented results from a study that suggests air pollution to accelerate carcinogenesis of EGFR-mutated lung epithelium cells in non-smokers [3].

Lung cancer in non-smokers (LCINS) is a disease with a low mutational burden, up to 10-fold fewer mutations, compared with lung cancer in (ever-)smokers. On the other hand, EGFR mutations are 4–5-fold more common in LCINS. Approximately half of the non-smokers with lung cancer have EGFR mutations in their cancer cells. Using biobank data from 447,932 individuals, Dr. Swanton and colleagues demonstrated an association between increasing exposure to airborne PM2.5 and the risk on 7 types of cancer, including NSCLC, gastrointestinal, and head-and-neck cancer. In addition, they showed an association between regional PM2.5 exposure and EGFR-mutated NSCLC.

Next, they showed PM2.5 exposure to increase the number of lung tumors in 3 mouse models with pre-existing EGFR or KRAS mutations, thereby proving causation. They also found that air pollution drives the influx of macrophages in lung tissue, releasing the inflammatory mediator IL-1β, which drives the expansion of EGFR-mutated cells in response to exposure to PM2.5. Of note, EGFR mutations or exposure to air pollution alone were not sufficient to drive this expansion. Moreover, blockade of IL-1β inhibited lung cancer initiation, which was consistent with data from a previous large clinical trial showing a dose-dependent reduction in lung cancer incidence when people were treated with the anti-IL-1β antibody canakinumab [4]. In addition, it was shown that also in healthy, never-smoking humans who were exposed to PM2.5 for some hours, IL-1β production by lung epithelial cells and macrophages was increased. Finally, the researchers demonstrated that activating EGFR and KRAS mutations are present in 15% and 53% of samples of lung tissue from healthy never-smokers, respectively. However, the incidence of these mutations is rare: about 1 in 600.000 cells, although their number increases with aging.

Dr. Swanson summarised that “cancer mutations exist in normal lung tissue and their incidence increase with age. Air pollution is, via IL-1β, likely a tumor promotor driving these mutated progenitor cells in a ‘cancer stem cell’ kind of state, eventually resulting in lung cancer. This data could pave the way to new molecular-based prevention approaches and development of targeted therapies for non-smokers who are at risk of lung cancer, i.e. those harbouring EGFR mutations.”

  1. Liu X, et al. Front Med. 2021;8:742076.
  2. Turner MC, et al. Cancer J Clin 2020;70:460–479.
  3. Swanton C, et al. Mechanism of action and an actionable inflammatory axis for air pollution-induced non-small cell lung cancer in never smokers. Abstract LBA1, ESMO Congress 2022, Paris, France, 09–13 September.
  4. Ridker PM, et al. Lancet 2017;390:1833–1842.

 

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