TY - JOUR
T1 - Neoantigen-directed immune escape in lung cancer evolution
AU - The TRACERx consortium
AU - Rosenthal, Rachel
AU - Cadieux, Elizabeth Larose
AU - Salgado, Roberto
AU - Bakir, Maise Al
AU - Moore, David A.
AU - Hiley, Crispin T.
AU - Lund, Tom
AU - Tanić, Miljana
AU - Reading, James L.
AU - Joshi, Kroopa
AU - Henry, Jake Y.
AU - Ghorani, Ehsan
AU - Wilson, Gareth A.
AU - Birkbak, Nicolai J.
AU - Jamal-Hanjani, Mariam
AU - Veeriah, Selvaraju
AU - Szallasi, Zoltan
AU - Loi, Sherene
AU - Hellmann, Matthew D.
AU - Laycock, Joanne
AU - Stone, Richard Kevin
AU - Lawrence, David
AU - Summers, Yvonne
AU - Califano, Raffaele
AU - Taylor, Paul
AU - Shah, Rajesh
AU - Booton, Richard
AU - Evison, Matthew
AU - Crosbie, Phil
AU - Joseph, Leena
AU - Bishop, Paul
AU - Quinn, Anne Marie
AU - Blackhall, Fiona
AU - Rogan, Jane
AU - Smith, Elaine
AU - Dive, Caroline
AU - Tugwood, Jonathan
AU - Rothwell, Dominic G.
AU - Gulati, Sakshi
AU - Moore, David A.
AU - Kerr, Keith
AU - Davies, Helen
AU - Danson, Sarah
AU - Edwards, John
AU - Chaturvedi, Anshuman
AU - Baker, Katie
AU - Carter, Mathew
AU - Krebs, Matthew G.
AU - Lindsay, Colin
AU - Booth, Sarah
PY - 2019
Y1 - 2019
N2 - 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.
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.
U2 - 10.1038/s41586-019-1032-7
DO - 10.1038/s41586-019-1032-7
M3 - Article
C2 - 30894752
AN - SCOPUS:85063265508
SN - 0028-0836
VL - 567
SP - 479
EP - 485
JO - Nature
JF - Nature
IS - 7749
ER -
