An immunogenetic basis for lung cancer risk

Area of Science:

• Immunology
• Genetics
• Oncology

Background:

• Cancer risk is multifactorial, involving inherited mutations, DNA errors, and environmental exposures.
• The role of genetic variation in immunosurveillance, particularly human leukocyte antigen (HLA) genes, in cancer risk remains unclear.

Purpose of the Study:

• To investigate the association between genetic variation in HLA-II loci and lung cancer risk, especially in smokers.
• To explore the functional implications of HLA-II genetic diversity and its changes in the context of smoking and lung cancer.

Main Methods:

• Analysis of population-level data from UK Biobank and FinnGen.
• Fine-mapping of HLA-II loci and amino acid variations.
• Single-cell RNA sequencing of lung tissue from smokers and lung cancer patients.

Main Results:

• Increased heterozygosity at HLA-II loci was associated with reduced lung cancer risk in smokers.
• Amino acid heterozygosity within the HLA-II peptide binding groove was implicated in this protective effect.
• Smoking induced proinflammatory lung macrophages and HLA-II expression in epithelial cells.
• Lung cancer cases showed widespread loss of HLA-II heterozygosity (LOH), favoring loss of alleles with diverse neopeptide repertoires.

Conclusions:

• Genetic variation in HLA-II, specifically heterozygosity, is a significant factor influencing lung cancer risk in smokers.
• Smoking alters the lung immune microenvironment and HLA-II expression.
• Loss of HLA-II heterozygosity in lung cancer suggests immune evasion mechanisms related to reduced antigen presentation diversity.