Lung cancer evolution is different in people who have and haven’t smoked

Australian scientists have discovered that the immune environments of smokers’ lungs are substantially different compared to people who have never smoked.

Their findings, published in Cancer Cell, may explain why only 20% of patients with lung cancer responded to immunotherapy treatment.

“There’s a very different inflammatory environment in the lungs of smokers compared to those who had never smoked,” says Professor Daniel Gray, from the Walter and Eliza Hall Institute (WEHI) of Medical Research in Australia, who co-led the research.

“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.”

Tissue-resident memory T cells (TRM) are a subset of T-cells – a type of white blood cell that helps your immune system fight infections and diseases. Memory T cells hang around after they’ve been exposed to an antigen, like one on the surface of a cancer cell, so that the next time they encounter it the immune system can launch a response more quickly.

TRM cells are non-circulating, instead they stay put in areas such as the gastrointestinal tract, skin, reproductive tract, and lungs.

This study suggests that, because there are a greater proportion of TRM cells in smoker lungs, tumours evolve and evade immunotherapy – a type of treatment that involves using the body’s own immune system to fight cancer.

Three scientists in white lab coats stand inside a laboratory. Lung
Left to right: Associate Professor Marie-Liesse Asselin-Labat (Theme Leader & Laboratory Head, Personalised Oncology division) Associate Professor Daniel Gray (Division Head, Gray Lab, Immunology division) and Dr Clare Weeden (Research Officer, Labat Lab, Personalised Oncology division). Credit: WEHI

“It shows that we need to take a different approach to treating smoker and non-smoker patients with lung cancer,” says co-lead author Marie-Liesse Asselin-Labat, Associate Professor at WEHI.

“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.”

The team are now looking to investigate ways to do this. 

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

Epigenetic silencing refers to the inactivation of genes, such as tumour suppressor genes in cancer cells, that occurs not through mutations in DNA, but through changes that affect the way your body reads it.

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

According to Dr Clare Weeden, another of the study’s lead researchers from WEHI, understanding the differences in tumour evolution is 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 concludes.

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