Study Suggests Role of Immunogenetic Associations in Lung Cancer Risk

New research recently published in Science examined immune-related genetic risk factors for lung cancer, specifically by studying variations in human leukocyte antigen (HLA) genes that help your body differentiate between self and non-self. HLA molecules are vital to the immune system’s ability to identify and destroy cancer cells.

In the United States, nearly 200,000 new cases of lung cancer were reported in 2020, with over 100,000 deaths. While the number of lung cancer deaths has generally decreased over the past 20 years, lung cancer remains the leading cause of cancer deaths in the US and is the third most common type of cancer.

About 80 to 90% of lung cancer deaths in the U.S. are attributed to smoking. The U.S. Preventive Services Task Force currently recommends yearly CT scans for lung cancer screening in certain adults at higher risk. This includes individuals aged 50 to 80 years old with a history of heavy smoking (20 pack-years or greater) who currently smoke or have quit in the last 15 years. Currently, no other screening tests are routinely recommended for lung cancer.

In the new study, the objective was to examine the impact of HLA heterozygosity (meaning different versions of a gene) on lung cancer risk at the population level, with the primary clinical endpoint being the first diagnosis or death due to lung cancer over an approximately 14-year follow up period.

“Our study more directly implicates the immune system as an important contributor to the risk of developing lung cancer,” researcher Robert Samstein, M.D., Ph.D., told MHE in an email interview. Samstein was one of the lead authors of the paper, along with Diego Chowell, Ph.D., and Hanna M. Ollila, Ph.D.

The researchers collected genetic and clinical data from the UK Biobank and validated with FinnGen, which consists of approximately 500,000 and 350,000 genotyped individuals, respectively. Genetic epidemiological and multimodal genomic data from these cohorts was analyzed.

Their results revealed that having heterozygosity (different gene variations) at HLA class II loci (HLA-II) was associated with a reduced risk of getting lung cancer. This association was seen in people who smoke or had a history of smoking, but not in those who never smoked. In people who smoked and developed lung cancer, a loss of genetic diversity was observed in these specific genes related to the immune system.

As the authors explain in their paper, these findings indicate an immunogenetic basis for the risk of lung cancer. A loss of genetic diversity in HLA genes suggests that there may be a functional relationship between the immune system's ability to detect and combat cancer cells and the risk of developing cancer, particularly in the context of lung cancer. Overall, the findings imply that the immune system's surveillance mechanisms related to HLA genes may play a role in determining an individual's susceptibility to cancer. The authors summarize in the article that these findings may support incorporating immunogenetic screening into lung cancer screening.

As discussed in a press release, the team plans on further researching the mechanism behind HLA heterozygosity’s protective effects and the role of non-classical CD4 T cells and HLA-II in the biology of cancer. This work may pave the way for more targeted approaches to cancer screening, prevention and treatment based on immune genetics — and may have implications beyond lung cancer.

“In the future, we may be able to target the immune system as a cancer prevention strategy,” Samstein stated.