Recent strides in cancer research have underscored the critical involvement of the immune system, particularly in the remarkable achievements of cancer immunotherapy.
A groundbreaking investigation spearheaded by scientists at the Icahn School of Medicine at Mount Sinai in New York, in collaboration with the University of Helsinki and Massachusetts General Hospital, has shed illuminating insights into how variations in immune genetics impact the risk of lung cancer. This study could potentially revolutionize prevention approaches and screening protocols.
The groundbreaking findings, unveiled in the February 22 online edition of Science, emerged from a comprehensive analysis blending genetic epidemiology and multimodal genomic assessments of data sourced from the UK Biobank, subsequently validated through FinnGen. At the heart of their exploration lay human leukocyte antigen (HLA) molecules, the most genetically diverse components of the human genome and pivotal players in immune recognition. These molecules encode proteins crucial for presenting foreign antigens on cell surfaces, aiding the immune system in identifying and eradicating threats, including cancer cells.
In a surprising twist, the study revealed that individuals exhibiting heterozygosity at HLA-II—harboring different gene variants—experienced a reduced risk of lung cancer, particularly pronounced among smokers, a demographic already predisposed to heightened lung cancer susceptibility owing to carcinogen exposure.
Diego Chowell, Ph.D., Assistant Professor of Oncological Sciences and Immunology and Immunotherapy at Icahn Mount Sinai and co-senior author of the study, remarks, “Our findings challenge conventional wisdom by spotlighting the significant role of immune genetics, specifically HLA-II heterozygosity, in mitigating lung cancer risk, especially among smokers.”
Moreover, integrating polygenic risk scores—reflecting genetic predisposition based on multiple genes—into the analysis heightened the lifetime lung cancer risk, particularly among smokers possessing identical versions of HLA-II genes.
This research transcends lung cancer, offering a fresh lens on cancer risk assessment. Dr. Chowell emphasizes that cancer's etiology extends beyond random mutations during DNA replication, inherited mutations, and environmental factors, incorporating the immune system as a crucial component.
Robert Samstein, MD, Ph.D., Assistant Professor of Radiation Oncology and Immunology and Immunotherapy at Icahn Mount Sinai and co-senior author of the study, notes, “Our findings represent a significant stride toward deciphering the intricate interplay between the immune system and cancer risk. Identifying individuals predisposed to heightened susceptibility based on immune genetics could enable targeted screening, prevention, and treatment approaches.”
The research team's future endeavors aim to delve deeper into the mechanisms underpinning HLA heterozygosity's protective effects, leveraging preclinical disease models. Furthermore, they aspire to unravel the roles of non-classical CD4 T cells and HLA class II in cancer biology, opening avenues for advancements in cancer mitigation and treatment.
Source: The Mount Sinai Hospital