Air pollution may cause lung cancer among never smokers

Data presented at the recent European Society for Medical Oncology (ESMO) Congress 2022 reveals a new mechanism by which very small pollutant particles in the air may cause lung cancer in people who have never smoked. The newly discovered pathway paves the way for the development of new prevention strategies and therapies, say the study authors. [Ann Oncol 2022;33(Suppl 7):S808–S869] 

The particles in question, which are typically found in vehicle exhaust and smoke from fossil fuels, are linked to the risk of non-small cell lung cancer (NSCLC) and account for over 250,000 lung cancer deaths annually worldwide. [Front Med (Lausanne) 2021;8:742076, CA Cancer J Clin 2020;70:460–479]

The new findings are based on human and laboratory research on mutations in the EGFR gene, which are found in approximately half of never-smokers with lung cancer. Exposure to increasing concentrations of airborne particulate matter less than 2.5 µm in diameter (PM_2.5) was associated with an increased risk of NSCLC with EGFR mutations in the study involving nearly half a million residents of England, South Korea, and Taiwan.

In laboratory studies, scientists from the Francis Crick Institute, UK, demonstrated that PM_2.5 promoted rapid changes in airway cells with EGFR mutations and in another gene linked to lung cancer called KRAS, driving them towards a state resembling cancer stem cells. In addition, they discovered that air pollution drives the influx of macrophages that release the inflammatory mediator interleukin-1 (IL-1), which drives the expansion of cells with EGFR mutations in response to exposure to PM_2.5. Subsequently, blocking IL-1 inhibited the initiation of lung cancer. Consistent with data from a previous large clinical trial demonstrating a dose-dependent reduction in lung cancer incidence in patients treated with the anti-IL1 antibody canakinumab, these findings demonstrated a dose-dependent decrease in lung cancer incidence. [Lancet 2017;390(10105):1833–1842]

“The same particles in the air that derive from the combustion of fossil fuels, exacerbating climate change, are directly impacting human health via an important and previously overlooked cancer-causing mechanism in lung cells. The risk of lung cancer from air pollution is lower than from smoking, but we have no control over what we all breathe. Globally, more people are exposed to unsafe levels of air pollution than to toxic chemicals in cigarette smoke, and these new data link the importance of addressing climate health to improving human health,” said Professor Dr Charles Swanton, of the Francis Crick Institute in London, UK. Swanton presented the research results during the Presidential Symposium of ESMO 2022.

In a final series of experiments, the researchers found EGFR and KRAS driver mutations in 18% and 33% of normal lung samples, respectively, using ultradeep mutational profiling. Swanton said: “We found that driver mutations in EGFR and KRAS genes, commonly found in lung cancers, are actually present in normal lung tissue and are a likely consequence of ageing. In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harbouring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t.”



Q&A with Professor Tony Mok, Li Shu Fan Medical Foundation Endowed Professor and Chairman of Department of Clinical Oncology at the Chinese University of Hong Kong, and Dr Anand Sachithanandan, Consultant Cardiothoracic Surgeon and president of Lung Cancer Network Malaysia.

Q: The press release announced that scientists have discovered how air pollution may trigger lung cancer in never-smokers. Firstly, how do you define a never-smoker?
Tony Mok (TM): Never-smokers are usually defined as the ones without habitual consumption of tobacco. For light smokers, it is usually defined as 10-pack year or less. Of course, there is always a grey area.

Anand Sachithanandan (AS): A history of tobacco consumption is rather subjective and often intentionally underreported by many patients. Another widely used ‘never-smoker’ definition is someone who has smoked < 100 cigarettes in their lifetime as per the US Centers for Disease Control criteria.

Q: The study identified a new mechanism through which very small pollutant particles in the air may trigger lung cancer in people who have never smoked – tell us more.
TM: PM_2.5 may induce inflammation in the cells that line the airway. One of the inflammatory factors is interleukin 1 beta. Professor Swanton’s group has established the link between these inflammatory factors and promotion of growth of EGFR mutation positive lung cancer cell.

AS: Traditionally, it was thought that healing of any chronic inflammatory process in the lungs may result in scarring or fibrosis that could predispose to the development of a cancer within the scarred tissue, decades later. The Francis Crick study however suggests a different pathogenesis by which inflammatory mediators effectively ‘activate’ pre-existing dormant driver cancer genes. 

Q: We have known about the link between pollution and lung cancer for a long time – how is this study different?
TM: The link between pollution and lung cancer was established by epidemiology data, meaning that the observation of higher incidence of lung cancer in more polluted countries. However, we have never confirmed the mechanism. We used to believe that PM_2.5 may cause mutation in the cells, but we were proven wrong. The current study provides new evidence suggesting PM_2.5 as an induction of promoter for lung cancer development.

AS: Pollutants causing the activation of pre-existing ‘cancer genes’ through the inflammatory process at a cellular level would help explain the rising incidence of lung cancer amongst nonsmokers and high case load observed even in young people, in polluted densely populated urban cities globally. 

Q: What implications does this have on the diagnosis and treatment of lung cancers?
TM: There is no immediate implication of lung cancer treatment and diagnosis, but there is huge potential on prevention and early detection of lung cancer.

AS: If these findings are further validated, it may open a whole new therapeutic approach with use of novel anti-inflammatory agents that attenuate or block the interleukin-mediated activation of driver mutations in nonsmokers deemed at risk for lung cancer. In terms of diagnosis, in addition to family history, targeted community screening with low dose CT imaging or artificial intelligence-led chest X-rays may prove beneficial in highly polluted cities, though admittedly such exposure may be difficult to quantify accurately.

Q: How does this new data provide new impetus in addressing climate health to improving human health?
TM: By better understanding of the mechanism of how pollution may induce lung cancer, policy makers should be more motivated to reduce the pollution as a means to improve human health.

AS: In terms of prevention, this should further incentivise global leaders and health authorities to promote and support the development and use of more sustainable, renewable and environment-friendly green technologies and energy sources to protect the health of our planet and all its peoples.