LBA1 - Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: Towards molecular cancer prevention

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).

Editorial acknowledgement

Legal entity responsible for the study

Francis Crick Institute and UCL Hospitals NHS Trust.

Funding

This work has been supported by the MarkFoundation ASPIRE I Award (Grant 21-029-ASP), Lung Cancer Research Foundation Grant on Disparities in Lung Cancer, ERC Advanced Grant (PROTEUS, Grant Agreement no. 835297), CRUK EDD (EDDPMA-Nov21100034), CRUK lung cancer centre of excellence infrastructure award, CRUK TRACERx grant and Rosetrees Out-of-round Award (OoR2020100009).

Disclosure

C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; 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, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, 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, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; 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, 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, Skyhawk Therapeutics; Financial Interests, Personal, Leadership Role: Break Through Cancer; Financial Interests, Institutional, Funding: Johnson & Johnson. J. Downward: Financial Interests, Personal, Other, consultant: AstraZeneca, Bayer, Jubilant, Theras, Vividion, Novartis; Financial Interests, Institutional, Research Grant: BMS, Revolution Medicines, 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, Astex Pharmaceutical; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; 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.