Particles linked to climate change also promote cancerous changes in airway cells
Cells with EGFR and KRAS gene mutations can turn cancerous when exposed to air pollutants
Late-breaking data pave way to new approaches to lung cancer prevention and treatment
Paris, France, 10 September 2022 - A new mechanism has been identified through which very small pollutant particles in the air may trigger lung cancer in people who have never smoked, paving the way to new prevention approaches and development of therapies, according to late-breaking data [to be] reported at the ESMO Congress 2022 by scientists of the Francis Crick Institute and University College London, funded by Cancer Research UK (1). The particles, which are typically found in vehicle exhaust and smoke from fossil fuels, are associated with non-small cell lung cancer (NSCLC) risk, accounting for over 250,000 lung cancer deaths globally per year (2,3).
“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 in lung cells. The risk of lung cancer from air pollution is lower than from smoking, but we have no control over what we all 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 Charles Swanton, the Francis Crick Institute and Cancer Research UK Chief Clinician, London, UK, who will present the research results at the ESMO 2022 Presidential Symposium on Saturday, 10 September.
The new findings are based on human and laboratory research on mutations in a gene called EGFR which are seen in about half of people with lung cancer who have never smoked. In a study of nearly half a million people living in England, South Korea and Taiwan, exposure to increasing concentrations of airborne particulate matter (PM) 2.5 micrometres (μm) in diameter was linked to increased risk of NSCLC with EGFR mutations.
In the laboratory studies, the Francis Crick Institute scientists showed that the same pollutant particles (PM2.5) promoted rapid changes in airway cells which had mutations in EGFR and in another gene linked to lung cancer called KRAS, driving them towards a cancer stem cell like state. They also found that air pollution drives the influx of macrophages which release the inflammatory mediator, interleukin-1β, driving the expansion of cells with the EGFR mutations in response to exposure to PM2.5, and that blockade of interleukin-1β inhibited lung cancer initiation. These findings were consistent with data from a previous large clinical trial showing a dose dependent reduction in lung cancer incidence when people were treated with the anti-IL1β antibody, canakinumab (4).
In a final series of experiments, the Francis Crick team used state-of-the-art, ultradeep mutational profiling of small samples of normal lung tissue and found EGFR and KRAS driver mutations in 18% and 33% of normal lung samples, respectively.
“We found that driver mutations in EGFR and KRAS genes, commonly found in lung cancers, are actually present in normal lung tissue and are a likely consequence of ageing. 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 harbouring 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,” said Swanton.
Commenting on the results, Tony Mok, Chinese University of Hong Kong, not involved in the study, 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 pre-cancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1β inhibitors. We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find non-smokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative.”
Like Swanton, he stresses the importance of reducing air pollution to lower the risk of lung diseases, including cancer. “We have known about the link between pollution and lung cancer for a long time, and we now have a possible explanation for it. As consumption of fossil fuels goes hand in hand with pollution and carbon emissions, we have a strong mandate for tackling these issues – for both environmental and health reasons,” Mok concluded.
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1 LBA1 ‘Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer in never smokers’ will be presented by Charles Swanton during Presidential Symposium 1 on Saturday, 10 September, 16:30 to 18:00 CEST in Paris Auditorium. Annals of Oncology, Volume 33 Supplement 7, September 2022
2 Liu X, Mubarik S, Wang S. Lung Cancer Death Attributable to Long-Term Ambient Particulate Matter (PM2.5) Exposure in East Asian Countries During 1990–2019. Frontiers in Medicine 2021 Oct 15;8:742076
3 Turner MC, Andersen ZJ, Baccarelli A et al. Outdoor Air Pollution and Cancer: An Overview of the Current Evidence and Public Health Recommendations. CA: Cancer J Clin 2020; 70: 460-479
4 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 Oct 21; 390 (10105): 1833-1842
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LBA1 - Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: towards molecular cancer prevention
C. Swanton1, W. Hill2, E. Lim3, C. Lee4, C.E. Weeden5, M. Augustine6, K. Chen7, F.-C. Kuan8, F. Marongiu9, F. Rodrigues10, H. Cha11, T. Jacks12, M. Luchtenborg13, I. Malanchi14, J. Downward15, C. Carlsten16, A. Hackshaw17, K.R. Litchfield18, J. DeGregori19, M. Jamal-Hanjani20
1Translational Cancer Therapeutics Department, Francis Crick Institute, London/United Kingdom, 2Cancer Evolution And Genome Instability Laboratory, Francis Crick Institute, London/United Kingdom, 3Cancer Evolution And Genome Instability Laboratory, The Francis Crick Institute, London/United Kingdom, 4Cegi, Francis Crick Institute, London/United Kingdom, 51 Midland Rd, The Francis Crick Institute, London/United Kingdom, 6Tumour Immunogenomics And Immunosurveillance, UCL - University College London, London/United Kingdom, 7Thoracic Surgery, Peking University People’s Hospital, Beijing/China, 8Hematology Oncology, Chang Gung Medical Foundation - Chiayi Chang Gung Memorial Hospital, Puzi City/Taiwan, 9Department Of Biochemistry & Molecular Genetics, UCHealth Cancer Care - Anschutz Medical Campus - University of Colorado Cancer Center, Aurora/United States of America, 10Tumour-host Interaction Laboratory, The Francis Crick Institute, London/United Kingdom, 11Division Of Hematology-oncology, Samsung Medical Center (SMC) - Sungkyunkwan University School of Medicine, Seoul/Korea, Republic of, 12The Jacks Lab, Koch Institute For Integrative Cancer Research at MIT, Cambridge/United States of America, 13National Cancer Registration And Analysis Service, Public Health England, London/United Kingdom, 14Tumour Host Interaction Lab, Francis Crick Institute, London/United Kingdom, 15Oncogene Biology Laboratory, The Francis Crick Institute, London/United Kingdom, 16Centre For Lung Health, UBC - The University of British Columbia, Vancouver/Canada, 17Clinical Trials, Cancer Research UK & University College London Cancer Trials Centre, London/United Kingdom, 18Tumour Immunogenomics And Immunosurveillance, UCL Cancer Institute - UCL - London's Global University, London/United Kingdom, 19Biochemistry And Molecular Genetics, UCHealth Cancer Care - Anschutz Medical Campus - University of Colorado Cancer Center, Aurora/United States of America, 20Medical Oncology Dept., UCL Cancer Institute - Paul O'Gorman Building, London/United Kingdom
Background: A mechanistic basis for non-small cell lung cancer (NSCLC) initiation in never smokers, a disease with a high frequency of EGFR mutations (EGFRm), is unknown. The air pollutant, particulate matter (PM), is known to be associated with the risk of NSCLC, however a direct cause and mechanism remain elusive.
Methods: We analysed 463,679 individuals to address the associations of increasing 2.5um PM (PM2.5) concentrations with cancer risk. We performed ultra-deep profiling of 247 normal lung tissue samples, analysed normal lung tissue from humans and mice following exposures to PM, and investigated the consequences of PM on tumour promotion in mouse lung cancer models.
Results: Increasing PM2.5 levels were associated with increased risk of EGFRm NSCLC in England, S.Korea and Taiwan and with increased risk of mesothelioma (HR=1.19), lung (HR=1.16), anal (HR=1.23), small intestine (HR=1.30), GBM (HR=1.19), lip, oral cavity and pharynx (HR: 1.15) and laryngeal carcinomas (HR=1.26) in UK Biobank; HR for each 1ug/m3 PM2.5 increment. 18-33% of normal lung tissue samples harbour driver mutations in EGFR and KRAS in the absence of malignancy. PM promotes a macrophage response and a progenitor-like state in lung epithelium harbouring mutant EGFR. Consistent with PM promoting NSCLC in at-risk epithelium harbouring driver mutations, PM increased tumour burden in three EGFR or KRAS driven lung cancer models in a dose-dependent manner. Finally, we uncover an actionable inflammatory axis driven by IL1B in response to PM, with anti-IL1B therapy preventing PM-induced mouse tumour formation, consistent with reductions in human lung cancer incidence with anti-IL1B therapy.
Conclusions: These results shed light on the aetiology of EGFRm lung cancer, particularly in never-smokers, and suggest that oncogenic mutations may be necessary but insufficient for tumour formation. These data reveal a mechanistic basis for PM driven lung cancer in the absence of classical carcinogen-driven mutagenesis, reminiscent of models of tumour initiation and promotion proposed 70 years ago, providing evidence to limit air pollution and opportunities for molecular targeted cancer prevention.
Clinical trial identification: TRAcking Non-small Cell Lung Cancer Evolution Through Therapy (Rx) (TRACERx) (NCT01888601) The PEACE (Posthumous Evaluation of Advanced Cancer Environment) Study (PEACE) (NCT03004755) Biomarkers and Dysplastic Respiratory Epithelium (NCT00900419)
Legal entity responsible for the study: Francis Crick Institute and UCL Hospitals NHS Trust
Funding: Foundation or academic group WITHOUT funding from a pharma, biotech, or other commercial company
- This work has been supported by the Mark Foundation ASPIRE I Award (Grant 21-029-ASP), Lung Cancer Research Foundation Grant on Disparities in Lung Cancer, Advanced Grant (PROTEUS, Grant Agreement no. 835297), CRUK EDD (EDDPMA-Nov21100034), and Rosetrees Out-of-round Award (OoR2020100009). E.L.L. receives funding from NovoNordisk Foundation (ID 16584), The Mark Foundation (Grant 21-029-ASP) and has been supported by Rosetrees. W.H is funded by an ERC Advanced Grant (PROTEUS, Grant Agreement no. 835297), CRUK EDD (EDDPMA-Nov21100034), The Mark Foundation (Grant 21-029-ASP) and has been supported by Rosetrees. K.C. is supported by Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences (2021RU002), National Natural Science Foundation of China (No.82072566) and Peking University People's Hospital Research and Development Funds (RS2019-01). T.K. receives grant support from JSPS Overseas Research Fellowships Program (202060447). S.H.L is supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C3006535), the National Cancer Center Grant (NCC1911269-3), and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HR20C0025). N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z) and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. J.D., M.G., Y.E.M. D.T.M. and R.L.K receive funding from American Association for Cancer Research/Johnson&Johnson (18-90-52-DEGR), and J.D. is supported by the Courtenay C. and Lucy Patten Davis Endowed Chair in Lung Cancer Research. M.G., Y.E.M. D.T.M. and R.L.K. were supported by National Cancer Institute (NCI) RO1 CA219893. E.J.E. was supported by NCI Ruth L. Kirschstein National Research Service Award T32-CA190216. The work at the University of Colorado was also supported by NCI Cancer Center Support Grant P30CA046934. M.J.-H. has received funding from Cancer Research UK, National Institute for Health Research, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Centre. C.S. is Royal Society Napier Research Professor. He is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorships Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF). This research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (835297) and Chromavision from the European Union’s Horizon 2020 research and innovation programme (665233). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (grant no. FC001112), the UK Medical Research Council (grant no. FC001112), and the Wellcome Trust (grant no. FC001112) and the European Research Council (grant no. ERC CoG-H2020-725492).
Disclosure:C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016.: Pfizer; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker, Activity took place in 2016.: Celgene; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Illumina; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board: Medicxi; Financial Interests, Personal, Invited Speaker: GlaxoSmithKline; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company.: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences; Financial Interests, Personal, Stocks/Shares: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021.: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies.: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee.: AstraZeneca; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019.: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, , Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, , Invited Speaker, From 2019: AACR; Non-Financial Interests, , Other, Board of Directors: AACR; Non-Financial Interests, , Advisory Role, EACR Advisory Council member: EACR. T. Jacks: Financial Interests, Personal, Member of the Board of Directors: Amgen; Financial Interests, Personal, Member of the Board of Directors: Thermo Fisher Scientific; Financial Interests, Personal, Advisory Board, co-Founder: Dragonfly Therapeutics; Financial Interests, Personal, Other, co-Founder: T2 Biosystems; Financial Interests, Personal, Advisory Board: SQZ Biotech; Financial Interests, Personal, Advisory Board: Skyhawk Therapeutics; Financial Interests, Personal, Leadership Role: Break Through Cancer; Financial Interests, Institutional, Funding: Johnson & Johnson. J. Downward: Financial Interests, Personal, Other, consultant: AstraZeneca; Financial Interests, Personal, Other, consultant: Bayer; Financial Interests, Personal, Other, consultant: Jubilant; Financial Interests, Personal, Other, consultant: Theras; Financial Interests, Personal, Other, consultant: Vividion; Financial Interests, Personal, Other, consultant: Novartis; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Revolution Medicines; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Monopteros Therapeutics; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: Bms. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster; Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Astex Pharmaceutical; Non-Financial Interests, , Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, , Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection.: Patent. All other authors have declared no conflicts of interest.
Annals of Oncology