Study reveals how patients’ smoking history changes evolution of lung cancer (EMBARGOED)

Understanding the differences in the evolution of lung cancer between smokers and non-smokers could be the key to unlocking new treatments.

Researchers from WEHI (Walter and Eliza Hall Institute of Medical Research) in Melbourne, Australia evaluated lung cancer progression in smokers, compared with people who had never smoked, and found substantial changes in the way the body responds.

The study helps explain why immunotherapy isn’t always effective in treating the disease.

At a glance

• Researchers observed very different inflammatory environments in the lungs of smokers compared to those who had never smoked. 
• A specific subset of T cells, called TRM, were highly enriched in smoker lungs, forcing any arising tumours to evolve and evade immunotherapy.
• The results highlight the importance of tailoring treatment for lung cancer patients, depending on their smoking history.

Of the 13,000 Australians diagnosed with lung cancer every year, 10% of men and 35% of women have no history of smoking.

The new research, published in Cancer Cell, was co-led by WEHI Associate Professor Marie-Liesse Asselin-Labat and Professor Daniel Gray.

Associate Professor Asselin-Labat 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.”  

Professor Gray said the research teams had 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 had 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.”

 Identifying new targets for lung cancer treatment

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.

“We are using genomic screening to look for epigenetic silencing that might occur so we can then focus on those targets,” Associate Professor Asselin-Labat said. 

“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, Dr Clare Weeden, said lung cancer did not only affect smokers, and understanding the differences in tumour evolution was vital to improving treatment. 

“Our work shows the importance of the environment a tumour develops in. 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,” she said.  

The research was a collaboration between WEHI, the Peter Doherty Institute for Infection and Immunity, the Royal Melbourne Hospital, the University of Melbourne, Austin Health and the Francis Crick Institute in London.

The research was supported by funding from the National Health and Medical Research Council, Australian Cancer Research Foundation (ACRF), the Lung Foundation Australia, Cure Cancer/Cancer Australia, the Harry Secomb Trust, the Jenny Tatchell Fund and the Victorian Cancer Agency

The study, ‘Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer’, is published in Cancer Cell (DOI: 10.1016/j.ccell.2023.03.019).

WEHI authors: Clare Weeden, Velimir Gayevskiy, Claire Marceaux, Daniel Batey, Tania Tan, Kenta Yokote, Nina Tubau Ribera, Charis Teh, Marie Trussart, Lucille Rankin, Jackson McDonald, Kate Sutherland, Tracy Leong, Terence Speed, Daniel Gray and Marie-Liesse Asselin-Labat.