Krishna et al. leveraged genetic and longitudinal clinical data from the FinnGen and UK Biobank, and found that heterozygosity at HLA-II loci is associated with reduced risk of lung cancer in both current and former, but not in never-smokers. Loss of heterozygosity (LOH) of the HLA-II loci favored the loss of alleles with larger neopeptide repertoires, and conferred substantial lifetime risk, independent of known clinical and genetic risk factors. Smoking affected HLA-II expressed in lung inflammatory macrophages and epithelial cells. Heterozygosity of amino acid sites within the HLA-II peptide binding groove was also associated with reduced risk of lung cancer.
Contributed by Shishir Pant
ABSTRACT: Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. (3)
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. (3) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (4) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (5) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (6) Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. (7) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (8) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (9) Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. (10) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (11) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (12) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (13) Research Unit for Evolutionary Immunogenomics, Department of Biology, Universitt Hamburg, 20146 Hamburg, Germany. (14) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (15) Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy. Stony Brook Cancer Center, Stony Brook University, New York, NY 11794, USA. (16) Vall d'Hebron Institute of Oncology, Barcelona 08035, Spain. Hartwig Medical Foundation, Amsterdam 1098 XH, the Netherlands. (17) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (18) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Radiation Oncology, Mount Sinai Hospital, New York, NY 10029, USA. (19) The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
