Si-Chong Han,Gui-Zhen Wang,Guang-Biao Zhou
Air pollution, EGFR mutation, and cancer initiation
Swanton et al. find that PM2.5 exposure is associated with EGFR/KRAS-driven lung cancer incidence. PM2.5 increases EGFR pre-mutated alveolar type II cell progenitor function and tumorigenic activity through interstitial macrophage-secreted IL-1β, providing potential prevention approaches to inhibit cancer initiation.
Air pollution, EGFR mutation, and cancer initiation

Swanton et al. find that PM2.5 exposure is associated with EGFR/KRAS-driven lung cancer incidence. PM2.5 increases EGFR pre-mutated alveolar type II cell progenitor function and tumorigenic activity through interstitial macrophage-secreted IL-1β, providing potential prevention approaches to inhibit cancer initiation.

According to the 2021 World Health Organization (WHO) Global Air Quality Guidelines (annual mean values of 5 μg/m3 for particulate matter [PM] equal to or smaller than 2.5 μm in diameter [PM2.5] and 15 μg/m3 for PM10, and 24-h mean values of 15 μg/m3 for PM2.5 and 45 μg/m3 for PM10), nearly all of the global population (>99%) breathes air that exceeds these guideline limits. Air pollution contains PM, carbon monoxide, ozone, nitrogen dioxide, and sulfur dioxide, while PM contains chemicals such as benzene, formaldehyde, and polycyclic aromatic hydrocarbons (benzo[a]pyrene [BaP] and others)., Ambient and household air pollution causes 6.8 million premature deaths annually worldwide, with 11% (748,000) of deaths attributed to lung cancer. PM2.5 induces genomic mutations and epigenetic modifications, and some molecules are critical for pollutant-induced carcinogenesis, because knockdown of which leads to inhibition of carcinogen-caused lung cancer in mice., However, how air pollution triggers cancer initiation and progression remains obscure, partially due to the complex nature of air pollutants and affected individuals’ exposure to tobacco/secondhand tobacco smoke, resulting in a lack of appropriate model for in-depth analysis. In the April 2023 issue of Nature, Charles Swanton and colleagues investigate the association between PM2.5 levels and incidence of lung cancer in never-smokers, which are usually lung adenocarcinoma and triggered by intrinsic mutations in a gene called epidermal growth factor receptor (EGFR). They also analyze the association between PM2.5 exposure time and lung cancer incidence. The authors carry out the study in 5 cohorts from England, South Korea, Taiwan region, Canada, and UK Biobank that contain 440,466 subjects of White and Asian ancestries, who were exposed to PM2.5 at low, intermediate, and relatively high levels. They find that nonsmokers with EGFR mutation living in high-pollution areas are more likely to develop lung cancer than those living in low-pollution areas, and 3 years of high PM2.5 exposure is sufficient to establish the connection between air pollution and lung cancer incidence (Figure 1A). These results indicate the significance of mitigation of air pollution in prevention of lung cancer. Cancers are believed to originate from a single cell that obtains somatic driver mutations. So far, no evidence suggests that environmental carcinogens could induce gain-of-function mutations in EGFR, though EGFR mutation rate in lung cancers from an air pollution region is higher than in affected individuals from less-polluted regions (38% vs. 27%; p = 0.14). Swanton et al. show that in 38 out of 195 (19%) affected individuals, the activating EGFR mutations are detected in non-cancerous lung tissues but not in counterpart tumor tissues. They further uncover that 54 out of 295 (18%) non-cancerous lung tissues harbor an EGFR driver mutation, and 43 out of 81 (53%) non-cancerous lung tissues harbor a KRAS driver mutation (Figure 1A). These unexpected results highlight the mutagenic effect of environmental pollutants on normal lung epithelial cells, and the biological functions of these somatic mutations in non-cancerous tissues, as well as their difference to that in cancerous tissues, warrant further investigation. Collectively, their results indicate that in the authors’ models, PM2.5 exposure and driver mutations represent two independent risk factors, which exert synergistic effects in the promotion of lung cancer. They then investigate the combined effects of PM2.5 exposure and pre-existing EGFR/KRAS mutation in murine models, which are clinically relevant. They show that PM2.5 significantly promotes EGFR/KRAS-driven lung tumorigenesis whether exposure occurs before or after oncogene induction. Mechanistically, they show that PM2.5 significantly increases the number of interstitial macrophages in the lung, which release interleukin-1β (IL-1β) to enhance the progenitor-like cell state within mutant EGFR-harboring lung alveolar type II (ATII) cells, the origin of lung adenocarcinoma. Interestingly, treatment with an anti-IL-1β antibody during PM2.5 exposure is able to inhibit formation of EGFR-driven lung adenocarcinoma (Figure 1B). These results demonstrate the critical roles of macrophage-IL-1β in PM2.5-cauced lung cancer and provide a potential target for prevention of this deadly disease. Overall, this study sheds new lights on air pollution-related lung carcinogenesis, showing that PM2.5 exposure increases the incidence of EGFR-driven lung cancer, which is believed to be associated with nonsmoker, Asian, women individuals. An important step forward by this work is that PM2.5 can induce the expansion of mutant EGFR pre-existing ATII cells through macrophage-IL-1β axis. This discovery is in line with our previous finding that deficiency in an inflammatory factor, CXCL13, inhibits BaP-induced lung cancer, though the roles of this and other cytokines/chemokines are not determined. These results indicate that targeting inflammatory pathways may limit the risk of tumor initiation and progression in those who are exposed to air pollution. Given that air pollution contains dozens of carcinogens, the one that induces the expression of IL-1β and PD-L1 in macrophages (Figure 1B) should be identified, and we guess that PAH compounds such as BaP might play a role because it is able to induce PD-L1 expression in lung epithelial cells. This possibility might be investigated in a future work. In addition, how air pollution induces lung cancer in affected individuals without pre-existing driver mutations remains an open question. More than 90% of lung cancer deaths are caused by air pollution and tobacco smoke, demonstrating the urgent need to elucidate environmental lung carcinogenesis, because these efforts can identify key molecules that can serve as drug targets for development of effective preventive and therapeutic strategies, to tame lung cancer. By dissecting lung adenocarcinoma promotion by air pollutants, Swanton and colleagues may further inspire research on environmental lung carcinogenesis, which will eventually help accelerate our conquering of lung cancer in the future.