Recent advances in cancer research have highlighted the vital role of the immune system, particularly in the notable successes of cancer immunotherapy.
Now, a paradigm-shifting study led by researchers at the Icahn School of Medicine at Mount Sinai in New York, in collaboration with the University of Helsinki and Massachusetts General Hospital, sheds light on how variations in immune genetics influence the risk of lung cancer, which could pave the way for improved prevention and screening strategies.
The findings were described in the Feb. 22 online edition of Science.
The researchers used genetic epidemiology and multimodal genomic analyzes of data from the UK Biobank, validating them in FinnGen. Their study focused on human leukocyte antigen (HLA) molecules, the most diverse genes in the human genome and which are the core of immune recognition. These genes contain instructions for making proteins, which play a crucial role in presenting foreign antigens on cell surfaces. This process helps the immune system identify and eliminate threats such as cancer cells.
Surprisingly, the study found that individuals with heterozygosity (having different versions of a gene) in HLA-II, rather than HLA-I, experienced a lower risk of lung cancer. This effect was particularly pronounced among smokers, a population that already has a higher risk of lung cancer due to exposure to carcinogens.
“Our findings challenge conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, plays an important 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. “In addition, when we added polygenic risk scores, which is a measure of genetic predisposition based on multiple genes, to the analysis, the lifetime risk of lung cancer increased, specifically in smokers who have identical versions of the HLA genes. -II. .
The implications of this research extend beyond lung cancer and offer a new perspective on cancer risk assessment, the researchers say. Conventional thinking about the causes of cancer is that the disease is caused by random mutations that arise during DNA replication, inherited mutations, and environmental factors. Research has shown that the immune system is also part of the etiology of cancer, says Dr. Chowell. By considering immune genetics along with hereditary and environmental factors, researchers aim to develop more effective prevention strategies, potentially harnessing the immune system to fight cancer.
“These results highlight a previously overlooked aspect of cancer risk assessment,” says co-senior author Robert Samstein, MD, PhD, assistant professor of Radiation Oncology and Immunology and Immunotherapy at Icahn Mount Sinai. “Our study marks a major 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 screening, prevention and treatment strategies.” more specific.”
Next, the research team plans to delve deeper into the mechanisms underlying the protective effects of HLA heterozygosity, focusing on preclinical disease models. Additionally, its goal is to explore the role of non-classical CD4 T cells and HLA class II in cancer biology, opening the door to possible advances in cancer mitigation and treatment.
The article is titled “An immunogenetic basis for lung cancer risk.”
The remaining authors of the paper, all with Icahn Mount Sinai except where noted, are: Chirag Krishna, PhD (Pfizer); Anniina Tervi, PhD (University of Helsinki); Miriam Saffern (PhD candidate); Eric A. Wilson, Ph.D.; Seong-Keun Yoo, PhD; Nina Mars, MD, PhD (University of Helsinki and The Broad Institute of Harvard and MIT); Vladimir Roudko, PhD; Byuri Angela Cho, PhD; Samuel Edward Jones, PhD (University of Helsinki); Natalie Vaninov (PhD candidate); Myvizhi Esai Selvan, PhD; Zeynep H Gu?mu?s, PhD; FinnGen Consortium; Tobias L. Lenz, PhD (University of Hamburg); Miriam Merad, MD, PhD; Paolo Boffetta, MD (Stony Brook University of New York and University of Bologna); Francisco Martínez-Jiménez, PhD (Stony Brook University of New York and Vall d'Hebron Oncology Institute, Barcelona); and Hanna M. Ollila, PhD (Massachusetts General Hospital, Harvard Medical School, The Broad Institute, and University of Helsinki).