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Lung Cancer Study Highlights Genetic Variants Involved in Immunosurveillance

NEW YORK – New research has identified differences in lung cancer risk that appear to coincide with genetic variation in a human leukocyte antigen (HLA) region of the immune system, highlighting the immune system's apparent importance early in the cancer development process.

"Through analysis of genetic epidemiological data from two large-scale population cohorts and of multimodal genomic data, our study suggests an immunogenetic basis for lung cancer risk," the study's authors wrote in Science on Thursday, noting that their new data "underscore the role of immunosurveillance in protecting against lung cancer."

Using UK Biobank and FinnGen participant data, the researchers searched for genetic variation coinciding with lung cancer diagnoses, focusing on polymorphic HLA class I and class II components of the adaptive immune system known for their role in preparing the antigens that immune T cells use to recognize potentially dangerous interlopers.

"With the recent success of immunotherapy as a potent cancer treatment, immunology and cancer biology have intimately intertwined," co-senior and co-corresponding author Robert Samstein, a precision medicine, immunology and immunotherapy, thoracic oncology, and radiation oncology researcher affiliated with the Icahn School of Medicine at Mount Sinai and Mount Sinai Hospital, said in an email. "However, how immune genetics effects cancer risk has not been fully explored."

"In lung cancer in particular, smoking, a known risk factor for lung cancer, sets off damage that activates the immune system," he explained. "We thought this would be the perfect setting to study the role of immunogenetics in cancer risk and ultimately lead to methods to harness the immune system for cancer prevention."

Based on imputed HLA genotypes for 391,182 UK Biobank participants, including 2,468 individuals with lung cancer, and 183,163 FinnGen participants (3,480 with lung cancer), the team saw dialed down lung cancer risk in individuals who carried heterozygous versions of HLA-II that are predicted to produce more diverse antigens in response to new mutations. That lung cancer-HLA-II relationship appeared to be particularly prominent in smokers or former smokers.

The imputed genotypes were backed up by available allele frequency and UK Biobank exome sequence data, the researchers reported, noting that "HLA-II heterozygosity is associated with reduced risk of lung cancer, which may account for the variability in lung cancer risk among current and former smokers."

Along with follow-up fine-mapping and structural analyses, the team performed single-cell RNA sequencing on tumor-adjacent, normal lung tissue from 19 smokers and eight never-smokers treated for lung cancer with surgical resection.

Together, the results revealed interactions between HLA-II functions in lung epithelial cells and proinflammatory activity by macrophage immune cells in the lung in response to smoking.

"Our study shows that the immune system has the ability to recognize [cancer-related] mutations and thus reveals that variations in the immune system is an overarching cancer risk factor," Samstein said.

Along with a clearer view of the immune system's role in cancer protection and motivation for future immune-based studies, the cancer-immune dynamics detected provide potential opportunities for everything from cancer prevention strategies that modulate immune function in at-risk individuals to enhanced cancer screening strategies in some individuals, he added.

Given such findings, for example, Samstein and his co-authors suggested that individuals who carry homozygous forms of HLA-II and have a history of smoking may benefit from low-dose computed tomographic (LDCT) screening at a younger age than HLA-II heterozygous smokers.

"Our study suggests that current or former smokers homozygous at HLA-II could be considered at an earlier age for [LDCT] screening, which may reduce lung cancer mortality," they wrote. "Whether the combination of genotype-driven risk assessment and LDCT reduces lung cancer mortality as compared with either method alone should be comprehensively investigated in a future prospective clinical trial."