Although it is well established that air pollution is associated with lung cancer, how this occurs has not been well described. For the first time, researchers have identified the mechanism by which particulate matter in the air may lead to non–small-cell lung cancer (NSCLC) in people who have never smoked. These findings, which were presented at the European Society for Medical Oncology (ESMO) Congress 2022, suggest that particulate matter in the air—which is also associated with climate change—is part of the etiology of NSCLC in never-smokers.
The researchers demonstrated that airborne particulate matter 2.5 micrometers in diameter increases the risk for NSCLC when EGFR mutations are present, which is in approximately 50% of never-smokers. Air pollutants trigger the release of the inflammatory mediator interleukin-1 beta (IL-1B) in cells with EGFR mutations to promote the development of lung cancer. These particles are typically found in vehicle exhaust and smoke from fossil fuels.
“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 on lung cells. The risk of lung cancer from air pollution is lower than from smoking [cigarettes], but we have no control over what we 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 lead investigator Charles Swanton, BSc, PhD, FRCP, Chief Clinician, Cancer Research UK, London, and Principal Group Leader, Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London.
The findings are based on a series of experimental and human studies in individuals with EGFR mutations. In a human study that included almost 474,000 people from England, South Korea, and Taiwan, researchers performed ultra-deep profiling of 247 normal lung tissue samples and analyzed normal lung tissue from humans and mice following exposures to particulate matter. EGFR and KRAS driver mutations were found in 15% and 53% of the normal lung tissue samples, respectively. Increasing levels of particulate matter 2.5 micrometers in diameter were associated with increased risk for EGFR mutation–positive NSCLC and mesothelioma.
“Particulate matter promotes a macrophage response and a progenitor-like state in lung epithelium harboring mutant EGFR. Consistent with these findings, exposure to particulate matter increased tumor burden in EGFR- or KRAS-driven lung cancer models in a dose-dependent manner,” Dr Swanton said.
The investigators found that IL-1B drives the inflammatory response to particulate matter. In mouse models, IL-1B therapy prevented tumor formation, suggesting that this approach could reduce the incidence of NSCLC driven by EGFR mutations.
“These results shed light on the etiology of EGFR-mutated NSCLC, particularly in never-smokers….in the absence of classical carcinogen-driven mutagenesis,” Dr Swanton said.
“The next step is to discover why some lung cells with mutations become cancerous when exposed to air pollutants while others don’t,” he added.
“This research is intriguing and exciting, as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and to try to reverse them with medicines such as IL-1B inhibitors. We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” said Tony Mok, BMSc, MD, FRCP(C), FRCP(Edin), FHKCP, FHKAM(Medicine), FASCO, Li Shu Fan Medical Foundation Endowed Professor and Chairman of the Department of Clinical Oncology, Chinese University of Hong Kong, in a statement from ESMO. Dr Mok was not involved in the study.
“As consumption of fossil fuels goes hand in hand with pollution and carbon emissions, we have a strong mandate for tackling these issues—both for environmental and health reasons,” he added.