Scientists Discover How Air Pollution May Trigger Lung Cancer in Never-Smokers [ESMO Congress 2022 Press Release]

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.