‘Sugar-coated’ tumour matrix may offer way to make triple-negative breast cancer easier to treat

Researchers at Barts Cancer Institute, Queen Mary University of London, have discovered a way in which the environment surrounding triple-negative breast cancer cells helps suppress our immune system, making this cancer harder to treat.

The study, published today (16th June) in Nature Communications, found that changes to sugar molecules on the protein scaffolding that surrounds tumour cells can influence whether immune cells can enter the tumour and how effectively they fight the cancer once there.

The findings open the door to a potential new treatment strategy that could make triple-negative breast cancers more vulnerable to the immune system and help more people to benefit from immunotherapy in future.

The challenges surrounding triple-negative breast cancer

Triple-negative breast cancer is one of the most challenging forms of breast cancer to treat. It grows and spreads quickly and does not respond to the hormone and protein-targeted therapies that work for other types of breast cancer. While new immunotherapies – treatments that harnesses the body’s own immune system to fight cancer – have improved outcomes for some people, they do not work for everyone. In many cases, the environment surrounding triple-negative breast cancers acts as a barrier, preventing the immune system from accessing and attacking the tumour.

Dr Oliver Pearce and his group at Barts Cancer Institute, Queen Mary University of London, study a component of this environment: the extracellular matrix, a scaffolding-like network of proteins that supports cells and helps tissues hold their shape. Previous research by the group suggested that sugar molecules, called glycans, which coat the proteins in this matrix, might play an important role in how tumours evade the immune system.

Dr Pearce, who is senior author of the new study, explains:

Small changes with large consequences

To investigate, the team analysed tumour samples from people with triple-negative breast cancer, examining gene activity, proteins, glycans and the location of immune cells within the tissue. They found significant differences between the extracellular matrix of tumour tissue and healthy tissue – including a notable increase in proteins coated with glycans in the tumour.

Crucially, these changes were linked to how immune cells behaved. In tumours with high levels of glycans, T cells – key cancer-fighting immune cells that identify, target, and destroy abnormal cells – were physically excluded from entering the tumour’s core.

To study this further, the researchers used a model they developed that uses real tumour tissue with all its cells removed, so that only the extracellular scaffolding remains. This allows them to introduce fresh immune and cancer cells into the existing tumour environment and observe exactly how it affects their behaviour.

They saw that T cells moved less freely through the tumour-derived matrix and struggled to penetrate into the tumour core. In addition, macrophages – immune cells that normally help T cells to tackle cancer – changed their behaviour when exposed to the tumour matrix. In doing so, they drove T cells into a state of exhaustion, where they become less effective in fighting cancer.

However, when the researchers used an enzyme to strip away specific glycan molecules from the tumour matrix, the effects were reversed: T cells could move freely into the tumour,  macrophage behaviour returned to normal, and T cell exhaustion reduced.

PhD student Ludovica Tarantola, co-first author of the study, said: