Neoantigen-directed immune escape in lung cancer evolutionMore about Open Access at the Crick
Authors listRachel Rosenthal Elizabeth Larose Cadieux Roberto Salgado Maise Al Bakir David A Moore Crispin Hiley Tom Lund Miljana Tanić James L Reading Kroopa Joshi Jake Y Henry Ehsan Ghorani Gareth Wilson Nicolai 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
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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.
Issue number 7749