biostudies-literatureKrishna CNIAID NIH HHSNCI NIH HHSNIH HHSeadi3808https://www.ebi.ac.uk/biostudies/studies/S-EPMC11998992biostudies-literatureUnknown383(6685)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 <i>human leukocyte antigen (HLA)</i>-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the <i>HLA</i>-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and <i>HLA</i>-II+ epithelial cells. In lung cancer, widespread loss of <i>HLA</i>-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. ThuScience (New York, N.Y.)An immunogenetic basis for lung cancer risk.PMC11998992DP5 OD028171R33 CA263705T32 AI078892R01 CA283469Selvan MEGumus ZHKrishna CMerad MRoudko VLenz TLWilson EASaffern MYoo SKMars NCho BAMartinez-Jimenez FChowell DVaninov NTervi AJones SEBoffetta PSamstein RMFinnGen§Ollila HMfalseAn immunogenetic basis for lung cancer risk.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 <i>human leukocyte antigen (HLA)</i>-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the <i>HLA</i>-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and <i>HLA</i>-II+ epithelial cells. In lung cancer, widespread loss of <i>HLA</i>-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thu2024-01-01T00:00:00Z2024 Feb2025-07-03T03:06:53.797Z2025-07-03T03:06:53.797ZS-EPMC119989923838672810.1126/science.adi3808