Smokers' Immune Genetic Feature Found to Lower Lung Cancer Risk

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Smokers’ Immune Genetic Feature Found to Lower Lung Cancer Risk

Smokers’ Immune Genetic Feature Found to Lower Lung Cancer Risk

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a unique protective immune characteristic in smokers that could help reduce their risk of lung cancer. The team found that heterozygosity in the HLA-II genetic locus can lower the risk of lung cancer in smokers.

It is well known that smoking is the primary cause of lung cancer, responsible for over 80% of lung cancer deaths. Smoking can lead to lung cancer through mechanisms such as DNA damage.

However, there are some individuals who seem to thrive even while smoking. Nature seems to maintain a balance, as the body has mechanisms to resist the risks associated with smoking.

This week, researchers from the Broad Institute and the Icahn School of Medicine published a paper in the journal Science, revealing a “special” protective immune characteristic found in smokers. This characteristic involves heterozygosity in the human leukocyte antigen (HLA)-II genetic locus.

Smokers' Immune Genetic Feature Found to Lower Lung Cancer Risk

This suggests that genetic variations in the immune surveillance system, like environmental exposures, genetic risks, DNA replication defects, are also features of cancer susceptibility. This also confirms that the human immune system, like in defending against pathogen infections, also plays a role in defending against cancer.

However, this does not mean that smokers can rest easy, as the risk is still much higher than non-smokers.

The immune surveillance hypothesis suggests that lymphocytes continuously search for tumor cells with new antigens caused by mutations, effectively triggering an immune response to eliminate developing cancer. However, there has been ongoing debate about whether the immune system can prevent cancer as it does with pathogens.

How does the immune system affect cancer development? GWAS studies have found an association between individual nucleotide polymorphisms (SNPs) involving HLA and susceptibility to lung cancer. HLA is a highly polymorphic set of genes that encode the major histocompatibility complex (MHC), which is crucial for antigen presentation and recognition.

There is the heterozygote advantage hypothesis in biological evolution. According to this theory, heterozygous HLA should provide more antigens for T cell recognition, thus more effectively clearing infected cells or cancer cells, leading to stronger disease protection. But is this really the case?

In this study, researchers hypothesized that heterozygous HLA genes are associated with a reduced risk of lung cancer. To verify this hypothesis, researchers analyzed data from two large population cohorts, the UK Biobank (N=391,182) and the Finnish FinnGen (N=183,163), integrating single-cell RNA sequencing data and lung cancer genomic maps, attempting to find HLA-mediated lung cancer protection mechanisms. Both databases have relatively complete individual-level genetic, environmental, and clinical longitudinal data, including HLA genotype data.

The main endpoint of the study was the first diagnosis or death due to lung cancer, with a follow-up period of about 14 years.

Researchers in the UK Biobank identified 2,468 eligible lung cancer patients, with the remaining individuals (N=384,928) serving as the control group. Consistent with other studies, adenocarcinoma was the most common histological subtype (N=700), followed by squamous cell carcinoma (N=338) and small cell carcinoma (N=192). Approximately 86.8% of lung cancer patients smoked or had smoked, with roughly equal gender distribution.

In FinnGen, 3,480 lung cancer patients were identified, with subtype distribution similar to that in the UK Biobank. However, the proportion of smokers differed, with 70.8% of lung cancer patients currently smoking in FinnGen, compared to 41.8% in the UK Biobank; the proportion of male lung cancer patients who smoked was also significantly higher than that of female patients (78.3% vs. 21.7%) in FinnGen, while it was more balanced in the UK Biobank.

Except for HLA-DQA1, the frequencies of other HLA alleles were comparable between the two cohorts.

The analysis results showed that heterozygosity in HLA-II was significantly higher in the control group compared to lung cancer patients, indicating that it is indeed associated with a reduced risk of lung cancer. Interestingly, the heterozygosity of the five HLA-II genes individually and the maximum heterozygosity of all genes had a protective effect, but this was not observed with HLA-I genes.

Researchers further analyzed the impact of HLA gene heterozygosity on the occurrence of lung cancer over a longer time scale. As expected, current smokers had the highest risk of developing lung cancer, followed by former smokers. In these two groups, a significant protective effect of HLA-II heterozygosity was observed, which was not enjoyed by non-smokers.

Conversely, homozygous HLA-II conferred a considerably higher lifetime risk of disease. For example, in the UK Biobank, the lifetime risk of developing lung cancer for current smokers with homozygous HLA-DRB1 was 13.9%, compared to 10.8% for those with heterozygous HLA-DRB1.

Single-cell RNA sequencing of adjacent normal lung cells showed that smoking led to upregulation of HLA-II and pro-inflammatory pathways in alveolar macrophages. Analysis of cancer genome maps (TCDA), pan-cancer whole-genome analysis (PCAWG), and data from the Hartwig Medical Foundation cohort confirmed widespread loss of heterozygosity (LOH) in HLA-II in lung cancer, which would favor immune escape by cancer cells.

These findings confirm that genetic variations in immune surveillance are as critical as environmental exposures, genetic risks, and DNA replication defects in cancer susceptibility. This expands our understanding of the role of the host immune system in cancer risk, and immunogenetics may become crucial for cancer screening.