The researchers have classified four different subtypes of environments found around lung tumours, each associated with different patterns of cancer progression. Those identified as having low levels of immune infiltration by T and B cells, but high levels of neutrophils, were more likely to spread to other parts of the body.  

Their work, published in Cancer Discovery and reported at the American Association for Cancer Research Annual Meeting 2024, is part of the Rubicon project, which aims to map out the immunology of lung cancer in detail to speed up the development of new treatments.

The tumour microenvironment is a mixture of cancer cells, immune cells, structural proteins and blood vessels. As the makeup of the microenvironment can vary throughout and around the tumour, looking at multiple sites of the tumour is helpful to get a more spatially accurate picture of what’s happening during the course of disease.

The team used advanced imaging techniques to map single cells and outline four different types of microenvironments in lung cancer, by investigating samples of tumours and normal tissue from 81 patients with non-small cell lung cancer (NSCLC) taking part in the TRACERx study.

Each class of microenvironment is composed of different amounts of immune cells in different areas of the tumour. They looked at T and B cells, macrophages and neutrophils.

In the fourth subtype, identified as having high levels of neutrophils, the researchers observed that tumours were also further away from a reliable blood supply. Subsequent evolutionary changes in these tumours enabled evasion from the T and B immune cells that are able to attack the cancer.

By comparing tumours likely and unlikely to spread, the researchers saw that the number of neutrophils was increased in tumours more likely to spread. They then used statistical and machine learning methods to confirm this association.

This suggests that measuring the number of neutrophils could be a good clinical test, helping doctors determine who might need additional treatment to prevent cancer spread.

Mihaela Angelova, postdoctoral fellow in the Cancer Evolution and Genome Stability lab at the Crick and co-senior author, said: “We’ve shown that high infiltration of neutrophils could be a marker for cancer evolution and spread. These tumours were genetically altered, separated from the blood supply and managed to evade the immune system, making them better able to spread.”

Charlie Swanton, Head of the Cancer Evolution lab and Chief Clinician at Cancer Research UK, said: “Lung cancer, particularly if caught at a later stage, is hard to treat, and mapping the environment around the tumour can help us to categorise cancers and work out personalised treatment strategies for patients.

“This research highlights the importance of pairing the evolutionary history of a tumour with information on how the tumour microenvironment organises in 3D to build the most accurate picture of an individual’s cancer.”

The researchers are now investigating what happens to the tumour microenvironment as the cancer metastasises – spreads and becomes genetically varied throughout the body.

This project was led by co-first authors Katey Enfield, Emma Colliver, Claudia Lee and Alastair Magness. It involved collaborations with Erik Sahai and Julian Downward’s laboratories, as well as the Flow Cytometry, Experimental Histopathology, Advanced Light Microscopy, Advanced Sequencing Facility and Scientific Computing STPs.

The Rubicon study is an Investigator-Sponsored Research (ISR) study, funded by Bristol Myers Squibb, and the TRACERx project is funded by Cancer Research UK.

Paul Mercer, Head of Collaboration at the Crick, said: “This has been a great example of multi partner collaboration with the Crick, UCL with Cancer Research UK and our industry partner BMS working together to support world-leading science, deepening our fundamental understanding of the tumour microenvironment for patient benefit.”