Researchers say they have identified a mechanism by which air pollution causes lung cancer in people who have never smoked.1
The researchers’ findings suggest that oncogenic mutations can occur in never-smokers as they age. These mutations and air pollution can work together to cause lung cancer in this patient population.
Specifically, the researchers found that air pollution promotes changes in cells with EGFR mutations that drive them toward a cancer stem cell-like state. Air pollution drives the recruitment of macrophages that release interleukin-1β (IL-1β), which drives the expansion of cells with EGFR mutations.
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These findings were presented at ESMO Congress 2022 by Charles Swanton, MD, PhD, of the Francis Crick Institute in London, UK.
Dr Swanton and colleagues first analyzed samples from 447,932 individuals in the UK Biobank to determine associations between cancer risk and varying concentrations of particulate matter measuring 2.5 micrometers or smaller (PM2.5).
The researchers found that higher PM2.5 concentrations were associated with a greater risk of cancers of the small intestine, anus/anal canal, larynx, lip/oral cavity/pharynx, and lung, as well as pleural mesothelioma and glioblastoma.
The researchers also found that increasing PM2.5 concentrations were significantly associated with EGFR-mutated lung cancer incidence in England, South Korea, Taiwan, and internationally.
To investigate this further, the researchers used mouse models. The team induced EGFR or KRAS mutations in mice and exposed the mice to PM2.5 or control. The mice exposed to PM2.5 had the same dose-dependent increase in the number of tumors or adenoma-to-carcinoma transition, regardless of the mutation type.
This suggests the association between PM2.5 and lung cancer is independent of the underlying driver mutation, Dr Swanton said.
To investigate this finding further, the researchers looked at alveolar type 2 (AT2) cells, which are thought to be one of the cells of origin for EGFR-mutant lung cancer. Additional experiments in mice revealed that pollution induces an AT2 transcriptional signature and produces more AT2 cells in these mice.
However, it was unclear if pollution enhances a stem cell/tissue progenitor state.
So the researchers assessed tissue stemness in epithelial cells from mice. The team compared EGFR-mutant epithelial cells with EGFR wild-type cells and evaluated the effects of pollution exposure.
This experiment revealed that neither air pollution alone nor EGFR mutations alone are sufficient to augment a stem cell state. Both are required.
To investigate how this happens, the researchers analyzed data from the COPA study (ClinicalTrials.gov Identifier: NCT02236039). In this study, healthy never-smokers were exposed to either PM2.5 for 2 hours or filtered air for 2 hours.
The researchers compared the transcriptional response to PM2.5 in patients from the COPA trial with the response in the mouse models, looking for common cytokines. IL-1β was upregulated in both species.
IL-1β is known to induce an AT2 progenitor state, and the researchers found that air pollution drives IL-1β expression from lung epithelium and alveolar macrophages. The researchers also found that IL-1β can mimic PM2.5 in a stem cell progenitor assay and overcome the need for pollutants.
“So, clearly, IL-1β looks like it’s the smoking gun,” Dr Swanton said.
To test this theory, the researchers treated mice with an anti-IL-1β antibody during PM2.5 exposure. In mice with EGFR mutations who were exposed to PM2.5, the anti-IL-1β antibody “completely abrogated” tumor growth, Dr Swanton said.
This is consistent with findings from the CANTOS trial, which showed a reduction in lung cancer incidence in patients treated with the anti-IL1β antibody, canakinumab.2
Lastly, Dr Swanton and colleagues analyzed healthy lung tissue from human never-smokers and found that 15% of samples contained EGFR activating mutations (exons 18 to 21), and 53% of samples contained KRAS activating mutations (exons 2 to 3).1
“We found that driver mutations in EGFR and KRAS … are actually present in normal lung tissue and are a likely consequence of aging,” Dr Swanton explained in a statement.3
“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 harboring 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.”
Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of disclosures.
References
- Swanton C, Hill W, Lim E, et al. Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: Towards molecular cancer prevention. Presented at ESMO 2022; September 9-13, 2022. Abstract LBA1.
- Ridker PM, MacFadyen JG, Thuren T et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: Exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390 (10105):1833-1842.
- Scientists discover how air pollution may trigger lung cancer in never-smokers. ESMO. News Release. Published September 10, 2022.
