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Heterozygosity in human leukocyte antigen (HLA) reduces risk of developing lung cancer, according to a new study led by researchers at the Icahn School of Medicine at Mount Sinai. Surprisingly, this effect was particularly pronounced among smokers. The researchers suggest that by considering immune genetics alongside hereditary and environmental factors, we can develop more effective prevention strategies and better use immunotherapies as cancer treatments.

This research was done in collaboration with the University of Helsinki and Massachusetts General Hospital. The findings were described in the February 22 online issue of Science.

“These results highlight a previously overlooked aspect of cancer risk assessment,” said co-senior author Robert Samstein, MD, PhD, assistant professor of radiation oncology, and immunology and immunotherapy at Icahn Mount Sinai. “Our study marks a big step toward understanding the intricate interplay between the immune system and cancer risk. We hope that by identifying individuals with increased susceptibility based on their immune genetics, we can implement more targeted screening, prevention, and treatment strategies.”

An estimated 2.2 million new lung cancer cases and 1.8 million lung cancer-related deaths occurred in 2020 worldwide, accounting for approximately 11.4% of the world’s total cancer cases and 18.0% of cancer deaths. 

HLA is expressed by the human major histocompatibility complex, which is the most complex known polymorphic system. The polymorphism and expression of HLA molecules is associated with the occurrence and development of tumors. HLA molecules can regulate the proliferation of tumor cells and inhibit antitumor immunity. 

These investigators used genetic epidemiology and multimodal genomic analyses of data from the UK Biobank, validating it in FinnGen. HLA contain instructions to make proteins play a crucial role in presenting foreign antigens on cell surfaces, thereby helping the immune system to identify and eliminate threats such as cancer cells.

This study found that individuals with heterozygosity at HLA-II, rather than HLA-I, experienced a decreased risk of lung cancer. This effect was particularly pronounced among smokers, a population already at higher risk for lung cancer due to exposure to carcinogens. Individuals who were current or former smokers benefited from this protective effect, but individuals who had never smoked did not. Also, smokers with lung cancer were found to have somatic loss of HLA class II heterozygosity

“Our findings challenge conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, plays a significant role in lung cancer risk, especially among smokers,” says co-senior author Diego Chowell, PhD, assistant professor of oncological sciences, and immunology and immunotherapy at Icahn Mount Sinai. “Further, when we added polygenic risk scores—which is a measure of genetic predisposition based on multiple genes—to the analysis, it increased the lifetime risk of lung cancer, specifically in smokers who have identical versions of the HLA-II genes.

The implications of this research, the authors say, extend beyond lung cancer, offering a new perspective on cancer risk assessment. Cancer is thought to be caused by random mutations arising during DNA replication, inherited mutations, and environmental factors. But immune genetics may also play a key role.

Next, the research team plans to delve deeper into the mechanisms underlying HLA heterozygosity’s protective effects, with a focus on preclinical models of disease. Additionally, they aim to explore the role of non-classical CD4 T cells and HLA class II in cancer biology.

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