Neoantigen directed immune escape in lung cancer evolution

doi:10.1038/s41586-019-1032-7

Published March 1, 2019 | Version v.1

Journal article Open

Neoantigen directed immune escape in lung cancer evolution

1. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, United Kingdom; Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, United Kingdom; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, United Kingdom
2. Cancer Genomics Laboratory. The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
3. Department of Pathology, GZA-ZNA, Antwerp, Belgium; Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
4. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, United Kingdom
5. Department of Pathology, UCL Cancer Institute, London, UK
6. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
7. Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK. ; Research Department of Haematology, University College London Cancer Institute, University College London, London, UK.
8. Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK
9. Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK; Research Department of Haematology, University College London Cancer Institute, University College London, London, UK
10. Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK

Abstract The interplay between an evolving cancer and the dynamic immune-microenvironment remains unclear. Here, we analyze 258 regions from 88 early-stage untreated non-small cell lung cancers (NSCLCs) using RNAseq and pathology tumor infiltrating lymphocyte estimates. The immunemicroenvironment was variable both between and within patients’ tumors. Diverse immune selection pressures were associated with different mechanisms of neoantigen presentation dysfunction restricted to distinct microenvironments. Sparsely infiltrated tumors exhibited evidence for historical immunoediting, with a waning of neoantigen-editing during tumor evolution, or copy number loss of historically clonal neoantigens. Immune-infiltrated tumor regions exhibited ongoing immunoediting, with either HLA LOH or depletion of expressed neoantigens. Promoter hypermethylation of genes harboring neoantigens was identified as an epigenetic mechanism of immunoediting. Our results suggest the immune-microenvironment exerts a strong selection pressure in early stage, untreated NSCLCs, producing multiple routes to immune evasion, which are clinically relevant, forecasting poor disease-free survival in multivariate analysis.

Notes

TRACERx Consortium are participate in this study. Authors thank to Royal Society Napier Research Professor. C.S is supported by the Francis Crick Institute (FC001169), the Medical Research Council (FC001169), and the Wellcome Trust (FC001169); by the UK Medical Research Council (grant reference MR/FC001169/1); 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, the University College London Hospitals Biomedical Research Centre, 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 (Grant Number 211179/Z/18/Z), and also receives funding from CRUK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals. 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), and Rosetrees. 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 results published here are in part based 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 No. phs000178.v9.p8). Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/.

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