Geographical exposures
Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.
And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.
Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.
He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
‘Elegant first demonstration’
“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.
“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.
Questions still to be answered include whether PM2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.
“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 try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.
“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,” he said in a statement.
The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.