Air pollution and lung cancer-A new era.

The incidence of lung cancer—a ‘Big 5’ lung disease as highlighted by the Forum of International Respiratory Societies (FIRS)1—is increasing in never-smoking individuals, as worldwide smoking rates decline, and the Tobacco Endgame is commenced in New Zealand.2-4 We must continue to focus on reducing tobacco consumption, the major risk factor for 80%–90% of lung cancers, however, while effective strategies are in place to reduce, detect, and treat smoking-related lung cancer,5, 6 our strategies in the never-smoking population are not well defined. A never-smoker is typically defined as someone who has smoked less than 100 cigarettes in their lifetime. While lung cancers in never smokers are predominantly adenocarcinoma, which is also the most common subtype currently, there are significant differences in the somatic mutations and mutational signatures in lung cancers in never smokers.7, 8 Clearly risk factors other than tobacco smoking play an important role in the carcinogenesis of never smokers diagnosed with lung cancer, including second hand smoke, radon, ionizing radiation, occupational hazards, chronic lung disease, domestic fuel smoke (biomass), diesel fumes, and air pollution.7, 9 Air pollution has long been associated with respiratory disease, and is now one of the leading causes of lung cancer other than cigarette smoking.10-12 It is estimated that 14% of total lung cancer cases in 2017 were attributable to exposure to air with high levels of fine particulate matter (PM) with the highest proportion of cases occurring in China (20.7%).11 Polluted air is made up of a heterogenous mix of heavy metals (such as lead), chemical compounds (such as carbon monoxide and nitrogen oxide) and PM.11, 13 PM refers to microscopic airborne particles of varying sizes however particles with a diameter ≤2.5 μm (PM2.5) are considered especially harmful as they penetrate deep into the respiratory bronchioles.14 PM2.5 levels are often used as a surrogate measure of air quality and have been associated with an increased risk of lung cancer development, so much so that an increase of 10 μg/m3 in ambient PM2.5 can cause a 15%–27% increase in lung cancer mortality risk.15-17 PM2.5 is produced largely as a result of fossil and biomass fuel combustion.18, 19 It therefore seems intuitive that an increase in human population would see an increase in PM2.5 given our reliance on combustibles in our everyday lives. A 2020 study investigating the changing of worldwide PM2.5 levels with increasing populations and urbanization identified India and China as two main centres of very high and increasing levels of PM2.5. An increase in PM2.5 with increased population and urbanization was similarly seen in other developing countries.20 High incidences of lung cancer (and other diseases) attributed to PM2.5 exposure have been reported in China and India in the last decade.21-27 Conversely, despite increasing population and urban development, developed countries such as Australia and the United States saw a reduction in ambient PM2.5, perhaps attributable to maintained vegetation greenness and anti-pollution measures, highlighting the viability of maintaining socioeconomic growth while also reducing PM2.5.20 PM2.5 is associated with an increased risk of lung cancer independent of smoking history.16, 28-31 A large UK Biobank cohort study of over 455,000 participants found a higher exposure category of pollution was associated with a 63% increased risk of lung cancer and an additive interaction between exposure and genetic risk scores,32 indicating a gene–environment contribution to susceptibility. Pathogenically, it is thought penetrating particles damage tissue by eliciting an inflammatory response in the alveoli promoting oncogene activation and carcinogenesis.33 However, the molecular pathways were unclear until a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022. Professor Charles Swanton reported their study of ~474,000 people from England, South Korea, and Taiwan found that increasing levels of PM2.5 were associated with an increased risk of EGFR-mutated NSCLC and mesothelioma, with the abstract suggesting a ~63% increased risk of lung cancer development.34 Surprisingly, ultradeep profiling of 247 normal lung tissue samples revealed EGFR and KRAS driver mutations in a subset of the normal lung tissue samples. The conventional paradigm is that these are somatically acquired mutations, with somatic and importantly actionable EGFR mutations being particularly prevalent in lung cancers from never smokers. Why some ‘normal’ cells house key oncogenic mutations is poorly understood; perhaps from ageing associated mutagenesis, but is a concept increasingly recognized in humans.35 The Swanton team also showed that in the lab, PM2.5 promoted rapid changes in airway cells, which had mutations in EGFR and KRAS, driving them towards a cancer stem cell like state. They also found that air pollution drives the influx of macrophages which release the responsible inflammatory mediator, interleukin-1 beta (IL-1β) which, when targeted with IL-1β blockade, saw the inhibition of lung cancer initiation, revealing a potentially targetable axis to prevent air pollution associated lung cancer. Notably, a previous clinical trial suggested a dose dependent reduction in lung cancer incidence with anti-IL1β antibody treatment.36 Worldwide air pollution has long been acknowledged as a cause for overall health concern, and recent evidence has associated rising levels of PM2.5 associated with air pollution as a primary driver of lung cancer development. While the risk of lung cancer from air pollution is lower than from tobacco smoking, we have to breathe the air around us, estimated about 10,000 L during a typical day for an adult, such that even low-level carcinogens in air can be very significant. A new era of improved understanding of air pollution-related lung cancer may lead to new interventions but prevention remains key as in tobacco smoke related lung cancers. Thus, improving air quality in heavily populated areas is a fundamental and urgent health priority, which will be the most effective strategy to combat this awful disease globally and locally. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. Henry M. Marshall is a member of the Asian Pacific Society of Respirology (APSR) Education Committee. Kwun M. Fong is Past President of the APSR. Edward K. H. Stephens and Venessa Chin have nothing to disclose.