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A pathway from air pollution to lung cancer in non-smokers identified

Presented by
Prof. Charles Swanton, University College London, UK
ESMO 2022
Increasing exposure to 2.5 µm particulate matter (PM2.5) raises the risk of non-small cell lung cancer (NSCLC) 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.

Lung cancer in non-smokers is a disease with a low mutational burden, translating to up to 10-fold fewer mutations compared with lung cancer in (ever-)smokers. On the other hand, approximately half of non-smokers with lung cancer have EGFR mutations in their cancer cells. Evidence links air pollution exposure to lung cancer incidence and mortality in non-smokers [1,2]. However, the molecular mechanism underlying this link has not been elucidated. Prof. Charles Swanton (University College London, UK) presented results from biobank data from 447,932 individuals [3].

Prof. Swanton and colleagues demonstrated an association between increasing exposure to airborne PM2.5 and the risk of 7 types of cancer, including NSCLC, gastrointestinal, and head-and-neck cancer. In addition, they showed an association between regional PM2.5 exposure and the incidence of EGFR-mutated NSCLC.

Proving causation, PM2.5 exposure increased the number of lung tumours in 3 distinct mouse models with pre-existing EGFR or KRAS mutations. Mechanistically, exposure to PM2.5 drives the influx of macrophages in lung tissue, releasing the inflammatory mediator IL-1β, which drives the expansion of EGFR-mutated cells. 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 the CANTOS trial (NCT01327846) showing a dose-dependent reduction in lung cancer incidence when people were treated with the anti-IL-1β antibody canakinumab [4]. In addition, Prof. Charles Swanton and colleagues could show that exposure to PM2.5 for some hours, increased IL-1β production by lung epithelial cells and macrophages in healthy, never-smoking humans. Finally, the researchers demonstrated that activating EGFR and KRAS mutations are present in respectively 15% and 53% of samples of lung tissue from healthy never-smokers. However, the incidence of these mutations is rare: about 1 in 600.000 cells, although their number increases with ageing.

Prof. Swanson summarised that “cancer mutations exist in normal lung tissue and their incidence increases with age. Air pollution is, via IL-1, likely a tumour promotor driving these mutated progenitor cells towards 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 (Lausanne). 2021;8:742076.
  2. Turner MC, et al. CA 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: Towards molecular cancer prevention. Abstract LBA1, ESMO Congress 2022, 09–13 September, Paris, France.
  4. Ridker PM, et al. Lancet. 2017;390(10105):1833–1842.

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