PMID- 30894752 OWN - NLM STAT- MEDLINE DCOM- 20191028 LR - 20240210 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 567 IP - 7749 DP - 2019 Mar TI - Neoantigen-directed immune escape in lung cancer evolution. PG - 479-485 LID - 10.1038/s41586-019-1032-7 [doi] AB - 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 immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival. FAU - Rosenthal, Rachel AU - Rosenthal R AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. AD - Bill Lyons Informatics Centre, University College London Cancer Institute, University College London, London, UK. AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Cadieux, Elizabeth Larose AU - Cadieux EL AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. FAU - Salgado, Roberto AU - Salgado R AD - Department of Pathology, GZA-ZNA, Antwerp, Belgium. AD - Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. FAU - Bakir, Maise Al AU - Bakir MA AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Moore, David A AU - Moore DA AD - Department of Pathology, University College London Cancer Institute, University College London, London, UK. FAU - Hiley, Crispin T AU - Hiley CT AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Lund, Tom AU - Lund T AD - Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. AD - Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. FAU - Tanic, Miljana AU - Tanic M AD - Department of Cancer Biology, University College London Cancer Institute, University College London, London, UK. FAU - Reading, James L AU - Reading JL AD - Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. AD - Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. FAU - Joshi, Kroopa AU - Joshi K AD - Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. AD - Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. FAU - Henry, Jake Y AU - Henry JY AD - Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. AD - Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. FAU - Ghorani, Ehsan AU - Ghorani E AD - Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. AD - Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. FAU - Wilson, Gareth A AU - Wilson GA AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Birkbak, Nicolai J AU - Birkbak NJ AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Jamal-Hanjani, Mariam AU - Jamal-Hanjani M AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. FAU - Veeriah, Selvaraju AU - Veeriah S AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. FAU - Szallasi, Zoltan AU - Szallasi Z AD - Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Danish Cancer Society Research Center, Copenhagen, Denmark. FAU - Loi, Sherene AU - Loi S AD - Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. FAU - Hellmann, Matthew D AU - Hellmann MD AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, Cornell University, New York, NY, USA. FAU - Feber, Andrew AU - Feber A AD - Division of Surgery and Interventional Science, University College London, London, UK. FAU - Chain, Benny AU - Chain B AD - Division of Infection and Immunity, University College London, London, UK. AD - Department of Computer Sciences, University College London, London, UK. FAU - Herrero, Javier AU - Herrero J AD - Bill Lyons Informatics Centre, University College London Cancer Institute, University College London, London, UK. FAU - Quezada, Sergio A AU - Quezada SA AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. AD - Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. AD - Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. FAU - Demeulemeester, Jonas AU - Demeulemeester J AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. AD - Department of Human Genetics, University of Leuven, Leuven, Belgium. FAU - Van Loo, Peter AU - Van Loo P AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. AD - Department of Human Genetics, University of Leuven, Leuven, Belgium. FAU - Beck, Stephan AU - Beck S AD - Department of Cancer Biology, University College London Cancer Institute, University College London, London, UK. FAU - McGranahan, Nicholas AU - McGranahan N AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Nicholas.McGranahan.10@ucl.ac.uk. AD - Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. Nicholas.McGranahan.10@ucl.ac.uk. FAU - Swanton, Charles AU - Swanton C AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Charles.Swanton@crick.ac.uk. AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Charles.Swanton@crick.ac.uk. CN - TRACERx consortium LA - eng GR - FC001169/MRC_/Medical Research Council/United Kingdom GR - 20265/CRUK_/Cancer Research UK/United Kingdom GR - FC001169/CRUK_/Cancer Research UK/United Kingdom GR - 20465/CRUK_/Cancer Research UK/United Kingdom GR - 24314/CRUK_/Cancer Research UK/United Kingdom GR - 19278/CRUK_/Cancer Research UK/United Kingdom GR - 23896/CRUK_/Cancer Research UK/United Kingdom GR - P30 CA008748/CA/NCI NIH HHS/United States GR - 28990/CRUK_/Cancer Research UK/United Kingdom GR - 22246/CRUK_/Cancer Research UK/United Kingdom GR - FC001202/MRC_/Medical Research Council/United Kingdom GR - 17786/CRUK_/Cancer Research UK/United Kingdom GR - 13-0316/AICR_/Worldwide Cancer Research/United Kingdom GR - FC001202/WT_/Wellcome Trust/United Kingdom GR - ERC_/European Research Council/International GR - 20764/CRUK_/Cancer Research UK/United Kingdom GR - 29420/CRUK_/Cancer Research UK/United Kingdom GR - 16463/CRUK_/Cancer Research UK/United Kingdom GR - MC_UP_1203/1/MRC_/Medical Research Council/United Kingdom GR - 21999/CRUK_/Cancer Research UK/United Kingdom GR - 24956/CRUK_/Cancer Research UK/United Kingdom GR - A20764/CRUK_/Cancer Research UK/United Kingdom GR - 20466/CRUK_/Cancer Research UK/United Kingdom GR - FC001169/WT_/Wellcome Trust/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - 29569/CRUK_/Cancer Research UK/United Kingdom GR - 30025/CRUK_/Cancer Research UK/United Kingdom GR - A22246/CRUK_/Cancer Research UK/United Kingdom GR - FC001202/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190320 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Antigens, Neoplasm) SB - IM CIN - Nat Rev Clin Oncol. 2019 May;16(5):271. PMID: 30926928 CIN - Nat Med. 2019 May;25(5):710. PMID: 31068709 CIN - Cancer Cell. 2019 May 13;35(5):711-713. PMID: 31085173 CIN - Br J Cancer. 2021 May;124(10):1615-1617. PMID: 33623078 MH - Adenocarcinoma/genetics/immunology/pathology MH - Antigen Presentation/immunology MH - Antigens, Neoplasm/genetics/*immunology MH - Carcinoma, Non-Small-Cell Lung/genetics/immunology/pathology MH - Carcinoma, Squamous Cell/genetics/immunology/pathology MH - Disease-Free Survival MH - *Evolution, Molecular MH - Female MH - Gene Expression Regulation, Neoplastic/genetics MH - Humans MH - Lung Neoplasms/genetics/*immunology/*pathology MH - Lymphocytes, Tumor-Infiltrating/immunology MH - Male MH - Prognosis MH - Tumor Escape/*immunology MH - Tumor Microenvironment/immunology PMC - PMC6954100 MID - EMS85285 COIS- The authors declare competing financial interests: C.S. receives grant support from Pfizer, AstraZeneca, BMS, and Ventana. C.S. has consulted for Boehringer Ingelheim, Eli Lily, Servier, Novartis, Roche-Genentech, GlaxoSmithKline, Pfizer, BMS, Celgene, AstraZeneca, Illumina, and Sarah Cannon Research Institute. C.S. is a shareholder of Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. S.A.Q. is a co-founder of Achilles Therapeutics. R.R., N.M., and G.A.W. have stock options and have consulted for Achilles Therapeutics. 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Wong YNS FIR - Georgiou, Andy IR - Georgiou A FIR - Quezada, Sergio IR - Quezada S FIR - Hartley, John A IR - Hartley JA FIR - Lowe, Helen L IR - Lowe HL FIR - Herrero, Javier IR - Herrero J FIR - Lawrence, David IR - Lawrence D FIR - Hayward, Martin IR - Hayward M FIR - Panagiotopoulos, Nikolaos IR - Panagiotopoulos N FIR - Falzon, Mary IR - Falzon M FIR - Borg, Elaine IR - Borg E FIR - Marafioti, Teresa IR - Marafioti T FIR - Janes, Sam M IR - Janes SM FIR - Forster, Martin IR - Forster M FIR - Ahmad, Tanya IR - Ahmad T FIR - Lee, Siow Ming IR - Lee SM FIR - Papadatos-Pastos, Dionysis IR - Papadatos-Pastos D FIR - Carnell, Dawn IR - Carnell D FIR - Mendes, Ruheena IR - Mendes R FIR - George, Jeremy IR - George J FIR - Ahmed, Asia IR - Ahmed A FIR - Taylor, Magali IR - Taylor M FIR - Choudhary, Junaid IR - Choudhary J FIR - Summers, Yvonne IR - Summers Y FIR - Califano, Raffaele IR - Califano R FIR - Taylor, Paul IR - Taylor P FIR - Shah, Rajesh IR - Shah R FIR - Krysiak, Piotr IR - Krysiak P FIR - 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Kerr, Amy IR - Kerr A FIR - Kadiri, Salma IR - Kadiri S FIR - Middleton, Gary IR - Middleton G FIR - Djearaman, Madava IR - Djearaman M FIR - Fennell, Dean IR - Fennell D FIR - Shaw, Jacqui A IR - Shaw JA FIR - Le Quesne, John IR - Le Quesne J FIR - Moore, David A IR - Moore DA FIR - Nakas, Apostolos IR - Nakas A FIR - Rathinam, Sridhar IR - Rathinam S FIR - Monteiro, William IR - Monteiro W FIR - Marshall, Hilary IR - Marshall H FIR - Nelson, Louise IR - Nelson L FIR - Riley, Joan IR - Riley J FIR - Primrose, Lindsay IR - Primrose L FIR - Martinson, Luke IR - Martinson L FIR - Anand, Girija IR - Anand G FIR - Khan, Sajid IR - Khan S FIR - Nicolson, Marianne IR - Nicolson M FIR - Kerr, Keith IR - Kerr K FIR - Palmer, Shirley IR - Palmer S FIR - Remmen, Hardy IR - Remmen H FIR - Miller, Joy IR - Miller J FIR - Buchan, Keith IR - Buchan K FIR - Chetty, Mahendran IR - Chetty M FIR - Gomersall, Lesley IR - Gomersall L FIR - Lester, Jason IR - Lester J FIR - Morgan, Fiona IR - Morgan F FIR - 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Ambrose L FIR - Devaraj, Anand IR - Devaraj A FIR - Chavan, Hema IR - Chavan H FIR - Nicholson, Andrew G IR - Nicholson AG FIR - Lau, Kelvin IR - Lau K FIR - Sheaff, Michael IR - Sheaff M FIR - Schmid, Peter IR - Schmid P FIR - Conibear, John IR - Conibear J FIR - Ezhil, Veni IR - Ezhil V FIR - Prakash, Vineet IR - Prakash V FIR - Russell, Peter IR - Russell P FIR - Light, Teresa IR - Light T FIR - Horey, Tracey IR - Horey T FIR - Danson, Sarah IR - Danson S FIR - Bury, Jonathan IR - Bury J FIR - Edwards, John IR - Edwards J FIR - Hill, Jennifer IR - Hill J FIR - Matthews, Sue IR - Matthews S FIR - Kitsanta, Yota IR - Kitsanta Y FIR - Suvarna, Kim IR - Suvarna K FIR - Fisher, Patricia IR - Fisher P FIR - Shackcloth, Michael IR - Shackcloth M FIR - Gosney, John IR - Gosney J FIR - Feeney, Sarah IR - Feeney S FIR - Asante-Siaw, Julius IR - Asante-Siaw J FIR - Ryanna, Kim IR - Ryanna K FIR - Dawson, Alan IR - Dawson A FIR - Tuffail, Mohamad IR - Tuffail M FIR - Bajaj, Amrita IR - Bajaj A FIR - Brozik, Jan IR - Brozik J FIR - Walter, Harriet IR - Walter H FIR - Carey, Nicolas IR - Carey N FIR - Price, Gillian IR - Price G FIR - Gilbert, Kayleigh IR - Gilbert K FIR - Webb, Joanne IR - Webb J FIR - Patel, Akshay IR - Patel A FIR - Chaturvedi, Anshuman IR - Chaturvedi A FIR - Granato, Felice IR - Granato F FIR - Baker, Katie IR - Baker K FIR - Carter, Mathew IR - Carter M FIR - Priest, Lynsey IR - Priest L FIR - Krebs, Matthew G IR - Krebs MG FIR - Lindsay, Colin IR - Lindsay C FIR - Gomes, Fabio IR - Gomes F FIR - Chemie, Francesca IR - Chemie F FIR - George, Robert IR - George R FIR - Patrini, Davide IR - Patrini D FIR - Khiroya, Reena IR - Khiroya R FIR - Shaw, Penny IR - Shaw P FIR - Skrzypski, Marcin IR - Skrzypski M FIR - Sunderland, Mariana Werner IR - Sunderland MW FIR - Reading, James L IR - Reading JL FIR - Beastall, Carmella IR - Beastall C FIR - Mangal, Nagina IR - Mangal N FIR - Peggs, Karl IR - Peggs K FIR - Lim, Emilia IR - Lim E FIR - Al-Bakir, Maise IR - Al-Bakir M FIR - Navani, Neal IR - Navani N FIR - Scarci, Marco IR - Scarci M FIR - Ensell, Leah IR - Ensell L FIR - Biswas, Dhruva IR - Biswas D FIR - Salgado, Roberto IR - Salgado R FIR - Razaq, Maryam IR - Razaq M FIR - Nicod, Jerome IR - Nicod J FIR - Beck, Stephan IR - Beck S FIR - Lopez, Saioa IR - Lopez S FIR - Huebner, Ariana IR - Huebner A FIR - Dietzen, Michelle IR - Dietzen M FIR - Mourikis, Thanos IR - Mourikis T FIR - Adefila-Ideozu, Toyin IR - Adefila-Ideozu T FIR - Begum, Sofina IR - Begum S FIR - Klein, Henriette IR - Klein H FIR - Mani, Aleksander IR - Mani A FIR - Carvalho, Soraia IR - Carvalho S FIR - Kaniu, Daniel IR - Kaniu D FIR - Realingo, Cristina IR - Realingo C FIR - Malima, Mpho IR - Malima M FIR - Booth, Sarah IR - Booth S FIR - Lim, Louise IR - Lim L FIR - Rao, Jagan IR - Rao J FIR - Tenconi, Sara IR - Tenconi S FIR - Socci, Laura IR - Socci L FIR - Kibutu, Faith IR - Kibutu F FIR - Agyemang, Michael IR - Agyemang M FIR - Young, Robin IR - Young R FIR - Blyth, Kevin G IR - Blyth KG FIR - Dick, Craig IR - Dick C FIR - Kirk, Alan IR - Kirk A FIR - Kidd, Andrew IR - Kidd A EDAT- 2019/03/22 06:00 MHDA- 2019/10/29 06:00 PMCR- 2020/01/10 CRDT- 2019/03/22 06:00 PHST- 2018/08/17 00:00 [received] PHST- 2019/02/21 00:00 [accepted] PHST- 2019/03/22 06:00 [pubmed] PHST- 2019/10/29 06:00 [medline] PHST- 2019/03/22 06:00 [entrez] PHST- 2020/01/10 00:00 [pmc-release] AID - 10.1038/s41586-019-1032-7 [pii] AID - 10.1038/s41586-019-1032-7 [doi] PST - ppublish SO - Nature. 2019 Mar;567(7749):479-485. doi: 10.1038/s41586-019-1032-7. Epub 2019 Mar 20.