Differences in lung cancer between smokers and non-smokers

Australian and UK researchers have evaluated lung cancer progression in smokers, compared with people who had never smoked, and found substantial changes in the way the body responds. Their study, published in the journal Cancer Cell, helps explain why immunotherapy isn’t always effective in treating the disease.

Of the 13,000 Australians diagnosed with lung cancer every year, 10% of men and 35% of women have no history of smoking. Study co-leader Associate Professor Marie-Liesse Asselin-Labat, from the Walter and Eliza Hall Institute (WEHI), said differences in the immune reactions between smokers and non-smokers may explain why only 20% of patients with lung cancer responded to immunotherapy treatment.

“It shows that we need to take a different approach to treating smoker and non-smoker patients with lung cancer,” she said.

“In smokers, we need to make the tumours visible to the immune system for immunotherapy to be effective, whereas in non-smoker patients we need to activate a dormant immune system to enable it to fight the tumour.”

Study co-leader Professor Daniel Gray, also from WEHI, said the researchers made interesting observations about the environment in which tumours grow and the difference in disease progression between smokers and non-smokers. “There’s a very different inflammatory environment in the lungs of smokers compared to those who have never smoked,” he said.

“We found a specific subset of T cells, called TRM, that are highly enriched in smokers. In these patients, the TRM apply pressure on the tumour to evade the body’s immune response.

“Immunotherapy is less effective against tumours that acquire this property.”

The researchers are now keen to investigate ways of increasing the visibility of the tumour cells to the immune system in lung cancer patients who have been smokers. Asselin-Labat said, “We are using genomic screening to look for epigenetic silencing that might occur so we can then focus on those targets. 

“This is the first step in developing precision, tailored therapies for specific patients depending on their smoking history.”

Another of the study’s lead researchers, WEHI’s Dr Clare Weeden, emphasised that lung cancer does not only affect smokers, and that understanding the differences in tumour evolution is vital to improving treatment.

“Our work shows the importance of the environment a tumour develops in,” she said. “If we can understand the nature of the pre-existing tissue, we can better work out how tumours evolve over time and develop precision therapy for individuals based on their smoking history.”

Immunofluorescence image shows the presence of a specific subset of T cells (tissue-resident memory T cells, TRM) in the lung of smoker patients. The TRM cells are represented here in aqua and red, the lung airways are depicted in pink and the cell nuclei are depicted in dark blue. Image credit: WEHI researchers.