Integrating genomic, transcriptomic, epigenomic, and pathologic data, Rosenthal et al. analyzed 258 regions from 88 untreated, early-stage NSCLC tumors. Immune infiltration varied significantly and was inversely correlated with subclonal mutation diversity both between and within patients. Neoantigens were silenced or eliminated under immune pressure via multiple mechanisms, including subclone loss, loss of heterozygosity in neoantigenic or antigen presentation genes, and hypermethylation (epigenetic silencing) of genes harboring neoantigenic mutations. Tumor capacity for immune evasion was prognostic.
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.
Author Info: (1) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Bill Lyons Informatics Centre, Universit
Author Info: (1) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Bill Lyons Informatics Centre, University College London Cancer Institute, University College London, London, UK. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (2) Cancer Genomics Laboratory, The Francis Crick Institute, London, 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, London, UK. (5) Department of Pathology, University College London Cancer Institute, University College London, 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, University College London 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. Research Department of Haematology, University College London Cancer Institute, University College London, London, UK. (11) 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. (12) 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. (13) 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. (14) 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. (15) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (16) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (17) Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Danish Cancer Society Research Center, Copenhagen, Denmark. (18) Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. (19) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Weill Cornell Medical College, Cornell University, New York, NY, USA. (20) Division of Surgery and Interventional Science, University College London, London, UK. (21) Division of Infection and Immunity, University College London, London, UK. Department of Computer Sciences, University College London, London, UK. (22) Bill Lyons Informatics Centre, University College London Cancer Institute, University College London, London, UK. (23) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. 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. (24) Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. Department of Human Genetics, University of Leuven, Leuven, Belgium. (25) Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. Department of Human Genetics, University of Leuven, Leuven, Belgium. (26) Department of Cancer Biology, University College London Cancer Institute, University College London, London, UK. (27) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Nicholas.McGranahan.10@ucl.ac.uk. Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. Nicholas.McGranahan.10@ucl.ac.uk. (28) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. Charles.Swanton@crick.ac.uk. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Charles.Swanton@crick.ac.uk.
