The Hidden Link Between Immune Genetics and Lung Cancer Risk

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The relationship between the immune system and cancer has been a subject of debate for years. While the cancer immune surveillance theory proposes that the adaptive immune system, particularly T cell-mediated recognition of neoantigens, can suppress early neoplasia, the evidence in humans is not as conclusive as in mice. However, recent studies have shed light on the potential role of genetic variation in the human leukocyte antigen (HLA) locus in preventing lung cancer.

The Hidden Link Between Immune Genetics and Lung Cancer Risk

Genetic Variation and Lung Cancer Risk.

Debating the Role of the Immune System in Cancer

The cancer immune surveillance theory posits that the immune system can naturally protect against cancer by recognizing and eliminating cancerous cells. This theory has been supported by studies in mice, which have shown that the adaptive immune system, particularly T cells, can recognize and destroy tumor cells. However, evidence in humans is limited, and the role of the immune system in preventing cancer is still a subject of debate.

Genetic Variation and Lung Cancer Risk

The HLA locus is a region of the genome that contains genes that encode proteins involved in the immune response. Genetic variation in this region has been linked to tumor evolution and treatment outcomes in lung cancer. This suggests that the immune system may play a role in preventing lung cancer by recognizing and eliminating cancerous cells.
The Hidden Link Between Immune Genetics and Lung Cancer Risk

Genetic Variation and Lung Cancer Risk

Understanding Cancer Risk

Understanding the factors that contribute to cancer risk is crucial for early detection and reducing mortality. One major risk factor for lung cancer is tobacco smoking, which increases the number of somatic mutations in the lungs, driving the development of cancerous cells. However, not all smokers develop lung cancer, suggesting that other factors, such as genetic variation, may play a role in determining an individual's risk.

HLA Heterozygote Advantage Theory

The HLA heterozygote advantage theory proposes that individuals with an HLA genotype that encodes two different allomorphs have a more diverse repertoire of antigenic peptides that they can present to the immune system. This diversity may enhance the immune system's ability to recognize and eliminate cancerous cells, thereby reducing the risk of developing cancer.

Results from UK Biobank and FinnGen

Analysis of data from the UK Biobank and FinnGen revealed that HLA class II (HLA-II) heterozygosity was associated with a reduced risk of lung cancer over more than a decade of follow-up. This effect was observed in both current and former smokers, suggesting that the immune system may play a role in protecting against lung cancer by recognizing and eliminating smoking-derived antigens.

HLA-II Homozygosity and Lifetime Risk of Lung Cancer

Conversely, HLA-II homozygosity was found to be a substantial risk factor for lung cancer, independent of other known risk factors. This suggests that individuals with this genotype may have a compromised immune response to cancerous cells, leading to an increased risk of developing lung cancer.

Conclusion

The association of HLA-II heterozygosity with a reduced risk of lung cancer highlights the potential role of genetic variation in immunosurveillance in determining an individual's susceptibility to cancer. These findings suggest that incorporating immunogenetics into lung cancer screening programs could help improve risk assessment and early detection, ultimately leading to better outcomes for patients.

Photo Credit: Science.


Reference: C. Krishna et al., Science 383, eadi3808 (2024). DOI: 10.1126/science.adi3808.

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