Genomic differences related to the immune system may play a key role in the early development of lung cancer. That finding, published, in Nature Communications, reveals potential for developing new therapeutics that could boost immune activity to prevent or halt progression of the disease, says the study's senior author. The newly identified genomic differences can be detected in normal airway tissue before any precancerous activity begins, which could potentially help physicians screen and monitor smokers who are at the highest risk of lung cancer.

More people die of lung cancer than from colon, breast, and prostate cancers combined--in the United States alone, lung cancer kills about 143,000 people each year. Worldwide, the number of people with the disease remains high and is growing in certain regions, and among women. In China, for example, 730,000 new cases of lung cancer were reported in 2015 and the number is expected to rise.

"The lung undergoes many changes prior to the development of [full-blown] lung cancer, so we have an opportunity to leverage those changes to both identify people at high risk for lung cancer and to intercept the disease process," says the lead and corresponding author of the Nature Communications study.

The new findings have identified four different genomic subtypes among current and former cigarette smokers who develop precancerous lesions. In people with the most problematic subtype, their immune response is impaired, says the senior author."That's one of the things that tumors do--prevent the immune system from attacking them. We think precancer cells might do that as well," the senior author says. "This opens up the opportunity to come in and find a way to train the immune system to eradicate those lesions."

In the study, scientists used bronchoscopes to take biopsies of precancerous lung lesions in current and former smokers, following the study participants over several years to see if their lesions progressed toward lung cancer or not. They identified biological changes within the lesions that indicated a higher risk of progression and showed that those lesions had reduced activity of genes related to certain kinds of immune cells.

The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions.

"This is an example where academia does the very basic discovery science--finding patients that have these early precancer lesions, biopsying them, and doing very deep molecular profiling, and the bioinformatics analysis," says the senior author. Then, from those academic findings, "industry can look at the data and figure out how to develop a therapeutic that will leverage that insight, that would reactivate the immune system to intercept the precancerous lesions from progressing to invasive lung cancer."

In addition to its other findings, the new study suggests that changes in aggressive precancerous lesions could be detected by "brushing," using a flexible brush to gather cells from the airway through the catheter of a bronchoscope, which is a much less invasive procedure than a traditional lung or airway biopsy.

"Normal-appearing cells in the airway can still show you the genomic signature," says the corresponding author. "It's early days, but maybe one day [we] could develop a simpler test to find someone who is incubating a lung cancer and [we'd] know who to treat to intercept lung cancer."

http://www.bu.edu/today/2019/iimmune-system-boost-could-prevent-lung-cancer/

https://www.nature.com/articles/s41467-019-09834-2

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmolecular-subtyping&filter=22