Neoantigen-directed immune escape in lung cancer evolution

Rachel Rosenthal, Elizabeth Larose Cadieux, Roberto Salgado, Maise Al Bakir, David A. Moore, Crispin T. Hiley, Tom Lund, Miljana Tanić, James L. Reading, Kroopa Joshi, Jake Y. Henry, Ehsan Ghorani, Gareth A. Wilson, Nicolai J. Birkbak, Mariam Jamal-Hanjani, Selvaraju Veeriah, Zoltan Szallasi, Sherene Loi, Matthew D. Hellmann, Andrew Feber, Benny Chain, Javier Herrero, Sergio A. Quezada, Jonas Demeulemeester, Peter Loo, Stephan Beck, Nicholas McGranahan () and Charles Swanton ()
Additional contact information
Rachel Rosenthal: University College London Cancer Institute, University College London
Elizabeth Larose Cadieux: The Francis Crick Institute
Roberto Salgado: GZA-ZNA
Maise Al Bakir: The Francis Crick Institute
David A. Moore: University College London Cancer Institute, University College London
Crispin T. Hiley: University College London Cancer Institute, University College London
Tom Lund: University College London Cancer Institute, University College London
Miljana Tanić: University College London Cancer Institute, University College London
James L. Reading: University College London Cancer Institute, University College London
Kroopa Joshi: University College London Cancer Institute, University College London
Jake Y. Henry: University College London Cancer Institute, University College London
Ehsan Ghorani: University College London Cancer Institute, University College London
Gareth A. Wilson: University College London Cancer Institute, University College London
Nicolai J. Birkbak: University College London Cancer Institute, University College London
Mariam Jamal-Hanjani: University College London Cancer Institute, University College London
Selvaraju Veeriah: University College London Cancer Institute, University College London
Zoltan Szallasi: Boston Children’s Hospital, Harvard Medical School
Sherene Loi: University of Melbourne
Matthew D. Hellmann: Memorial Sloan Kettering Cancer Center
Andrew Feber: University College London
Benny Chain: University College London
Javier Herrero: University College London Cancer Institute, University College London
Sergio A. Quezada: University College London Cancer Institute, University College London
Jonas Demeulemeester: The Francis Crick Institute
Peter Loo: The Francis Crick Institute
Stephan Beck: University College London Cancer Institute, University College London
Nicholas McGranahan: University College London Cancer Institute, University College London
Charles Swanton: University College London Cancer Institute, University College London

Nature, 2019, vol. 567, issue 7749, 479-485

Abstract: 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 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.

Date: 2019
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DOI: 10.1038/s41586-019-1032-7

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