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Neoantigen-directed immune escape in lung cancer evolution

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journal contribution
posted on 28.10.2020, 14:00 by 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 Van Loo, Stephan Beck, Nicholas McGranahan, Charles Swanton, The TRACERx Consortium
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.

Funding

Crick (Grant ID: 10169, Grant title: Swanton FC001169) European Research Council (Grant ID: 617844 - THESEUS, Grant title: ERC 617844 - THESEUS) Crick (Grant ID: 10202, Grant title: Van Loo FC001202)

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