Neoantigen-directed immune escape in lung cancer evolution

R Rosenthal; EL Cadieux; R Salgado; M Al-Bakir; DA Moore; CT Hiley; T Lund; M Tanić; JL Reading; K Joshi; JY Henry; E Ghorani; GA Wilson; NJ Birkbak; M Jamal-Hanjani; S Veeriah; Z Szallasi; S Loi; MD Hellmann; A Feber; B Chain; J Herrero; SA Quezada; J Demeulemeester; P Van Loo; S Beck; N McGranahan; C Swanton; J Czyzewska-Khan; D Johnson; J Laycock; P Gorman; RE Hynds; TBK Watkins; M Escudero; A Stewart; A Rowan; C Abbosh; J Goldman; RK Stone; T Denner; S Ward; E Nye; YNS Wong; A Georgiou; HL Lowe; D Lawrence; M Hayward; N Panagiotopoulos; M Falzon; E Borg; T Marafioti; SM Janes; M Forster; T Ahmad; SM Lee; D Papadatos-Pastos; D Carnell; R Mendes; J George; A Ahmed; M Taylor; J Choudhary; Y Summers; R Califano; P Taylor; R Shah; P Krysiak; K Rammohan; E Fontaine; R Booton; M Evison; P Crosbie; S Moss; L Joseph; P Bishop; AM Quinn; H Doran; A Leek; P Harrison; K Moore; R Waddington; J Novasio; F Blackhall; J Rogan; E Smith; C Dive; J Tugwood; G Brady

Journal article

Neoantigen-directed immune escape in lung cancer evolution

R Rosenthal, EL Cadieux, R Salgado, M Al-Bakir, DA Moore, CT Hiley, T Lund, M Tanić, JL Reading, K Joshi, JY Henry, E Ghorani, GA Wilson, NJ Birkbak, M Jamal-Hanjani, S Veeriah, Z Szallasi, S Loi, MD Hellmann, A Feber Show all

Nature | NATURE PORTFOLIO | Published : 2019

DOI: 10.1038/s41586-019-1032-7

Abstract

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoeditin..

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University of Melbourne Researchers

Sherene Loi Author

Roberto Salgado Author Medicine - Royal Melbourne Hospital

Grants

Awarded by Rosetrees Trust

Funding Acknowledgements

We thank the members of the TRACERx consortium for participating in this study. C.S. is Royal Society Napier Research Professor. C.S. is supported by the Francis Crick Institute, which receives its core funding from the Medical Research Council (FC001169), the Wellcome Trust (FC001169), and Cancer Research UK (FC001169). C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet-607722), Chromavision (this project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 665233), National Institute for Health Research (NIHR), the University College London Hospitals Biomedical Research Centre (BRC) and the Cancer Research UK University College London Experimental Cancer Medicine Centre. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z), and also receives funding from CRUK Lung Cancer Centre of Excellence, Rosetrees and the University College London Hospitals Biomedical Research Centre (BRC) and the Cancer Research UK University College London Experimental Cancer Medicine Centre. E.L.C., J.D. and P.V.L. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. J.D. is a postdoctoral fellow of the Research Foundation -Flanders (FWO). S.A.Q. is funded by a CRUK Senior Cancer Research Fellowship (C36463/A22246), a CRUK Biotherapeutic Program Grant (C36463/A20764), the Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265) and Rosetrees. M.T. received funding from the People Programme Marie Curie Actions (FP7/2007-2013/WHRI-ACADEMY-608765) and the Danish Council for Strategic Research (1309-00006B). The TRACERx study (Clinicaltrials. gov no: NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). TRACERx is funded by Cancer Research UK (C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. For the RRBS methylation data, we acknowledge technical support from the CRUK-UCL Centre-funded Genomics and Genome Engineering Core Facility of the UCL Cancer Institute and grant support from the NIHR BRC (BRC275/CN/SB/101330). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The results published here are based in part upon data generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. The data were retrieved through database of Genotypes and Phenotypes (dbGaP) authorization (accession number phs000178.v9.p8). Information about TCGA and the constituent investigators and institutions the TCGA research network can be found at http://cancergenome.nih.gov/.