Impact of immune genetics on cancer

Cancer detection and screening as a treatment for malignant cells with a biopsy or testing caused by carcinogens and genetics with a cancerous cell as an immunotherapy symbol as a 3D render.

Prior cancer research has expressed the essential role of the immune system, particularly its function in cancer immunotherapy. A recent study provides additional insight on how differences in immune genetics can increase or decrease a person’s risk of lung cancer. The research team, led by scientists at the Icahn School of Medicine at Mount Sinai in New York, published its findings in the Feb. 22 online issue of Science. A primary outcome of the study is its potential to enhance screening and prevention strategies. 

The study focused on human leukocyte antigen (HLA) molecules, which are the most diverse genes in the human genome and are at the core of immune recognition. HLA genes contain instructions to make proteins that play a crucial role in presenting foreign antigens on cell surfaces. This process aids the immune system in identifying and eliminating threats, such as cancer cells. Investigators utilized genetic epidemiology and multimodal genomic analyses of data pulled from the UK Biobank and validated in FinnGen.

Results demonstrate that having a variety of HLA-II genes helps to produce tobacco-related antigens that support early cancer detection. Therefore, individuals who have different versions of HLA-II, rather than HLA-I, are at a decreased risk of lung cancer. The paper indicates that this is more noticeable in smokers than non-smokers and is an important discovery for a population already at higher risk of lung cancer due to carcinogenic exposure. 

“Our findings challenge conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, play a significant role in lung cancer risk, especially among smokers,” said Diego Chowell, PhD, co-senior author of the paper and 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.”

Dr. Chowell said the research proves that the etiology of cancer goes beyond the conventional disease causes (environmental factors, inherited gene mutations and random mutations occurring during DNA replication) to include the immune system. Scientists believe this knowledge offers a new outlook on assessing cancer risk, and could lead to the development of more effective prevention strategies that involve harnessing the immune system to combat cancer. 

“These results highlight a previously overlooked aspect of cancer risk assessment,” said Robert Samstein, MD, PhD, co-senior author and 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.”

Drs. Chowell and Samstein, along with their colleagues at Icahn Mount Sinai, collaborated with researchers at the University of Helsinki, Massachusetts General Hospital and the Broad Institute of MIT and Harvard. The team plans to further investigate the mechanisms underlying HLA heterozygosity's protective properties, with a focus on preclinical models of disease. Scientists also seek to explore the role of non-classical CD4 T cells and HLA class II in cancer biology, opening the door for advancements in the mitigation and treatment of cancer.

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