Recent advances in cancer research have highlighted the critical role of the immune system, particularly in the remarkable successes of cancer immunotherapy.

Now, a paradigm-changing 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 affect lung cancer risk. Do, potentially pave the way. for better prevention strategies and screening.

The findings were reported in the February 22 online issue of science

The investigators used genetic epidemiology and multimodal genomic analyzes of data from the UK Biobank, validated at FinnGen. Their study focused on human leukocyte antigen (HLA) molecules—the most diverse genes in the human genome and central to immune recognition. These genes contain instructions for making proteins, which play an important 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-II had a reduced risk of lung cancer. This effect was particularly pronounced in smokers, a population already at increased risk of developing lung cancer.

“Our findings challenge conventional thinking by showing that immune genetics, particularly HLA-II heterozygosity, play an important role in lung cancer risk, particularly in smokers,” co-senior author says Diego Chuval, PhD, assistant professor of oncological sciences, and immunology. and Icahn immunotherapy at Mount Sinai. “Furthermore, when we included polygenic risk scores — a measure of genetic predisposition based on multiple genes — in the analysis, it increased the lifetime risk of lung cancer, especially But in smokers who have the same version of the HLA-II gene.

The researchers say the implications of this research extend beyond lung cancer, offering a new perspective on cancer risk assessment. Conventional thinking about the causes of cancer is that the disease is caused by random mutations that occur 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 Chowal. By considering immune genetics along with hereditary and environmental factors, investigators aim to develop more effective prevention strategies, potentially harnessing the immune system to fight cancer.

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

Next, the research team plans to delve deeper into the mechanisms underlying the protective effects of HLA heterozygosity, focusing on early disease patterns. Additionally, they aim to explore the role of non-classical CD4 T cells and HLA class II in cancer biology, opening the door to potential advances in cancer mitigation and treatment.

The paper is titled “An Immunogenetic Basis for Lung Cancer Risk.”

The remaining authors of the paper, all with Icahn Mount Sinai except where indicated, are: Chirag Krishna, PhD (Pfizer); Annina Tarvi, PhD (University of Helsinki); Mary Safran (PhD candidate); Eric A. Wilson, PhD; Seung-Kyun Yoo, PhD; Nina Mars, MD, PhD (University of Helsinki and The Broad Institute of Harvard and MIT); Vladimir Rudko, PhD; Bury Angela Chu, PhD; Samuel Edward Jones, PhD (University of Helsinki); Natalie Vaninoff (PhD candidate); Muse Esai Selvan, Ph.D.; Zeynep H Gu?mu?s, PhD; FinnGen Consortium; Tobias L. Lenz, PhD (University of Hamburg); Maryam Mirad, MD, PhD; Paolo Boffetta, MD (Stony Brook University in New York and University of Bologna); Francisco Marti?nez-Jime?nez, PhD (Stony Brook University in New York and Val d’Hebron Institute of Oncology, Barcelona); and Hanna M. Olella, PhD (Massachusetts General Hospital, Harvard Medical School, The Broad Institute, and University of Helsinki).