Blocking SLAMF6 enables T cells to kill leukaemia cells

A research team at Lund University has discovered a mechanism that allows acute myeloid leukaemia (AML) cells to evade the body’s immune system. By developing an antibody that blocks this mechanism, the researchers successfully restored the immune system’s ability to kill the cancer cells in mice and laboratory trials. Their findings are published in Nature Cancer.

Immunotherapy’s challenge in leukaemia

Immunotherapy has changed the treatment paradigm of many cancers, but progress has been limited in leukaemia. AML is particularly difficult to treat, with a five-year survival rate of just over 30 percent. Furthermore, existing treatments are often aggressive – combining strong chemotherapy with stem cell transplantation.

Targeting leukaemia stem cells

“We wanted to see if we could find surface proteins unique to leukaemia stem cells, which would therefore act as interesting targets for a targeted treatment. If such proteins were not present on healthy blood stem cells it might be possible to attack the tumour – without harming the healthy blood system,” says Thoas Fioretos, research group leader and Professor of Clinical Genetics at Lund University.

In their study, the researchers identified a previously unknown surface protein expressed on leukaemia stem cells, but not on healthy blood stem cells. This discovery was enabled by large-scale protein mapping in bone marrow samples from three patients with particularly intractable AML. Comparisons with healthy blood stem cells revealed that the surface protein, SLAMF6, was exclusively expressed on the diseased cells. This finding was then validated in an additional 50 AML patients.

How SLAMF6 helps cancer evade the immune system

The researchers investigated the function of SLAMF6 using CRISPR/Cas9 gene editing. The protein was shown to play a central role in how cancer cells avoid detection by the immune system’s T cells – allowing the cancer to grow undisturbed.

“When we blocked the surface protein, using a specific antibody we developed in cooperation with the SciLifeLab Drug Discovery and Development Platform, the T cells could suddenly detect and kill the cancer cells – both in test tubes and in mice,” said Carl Sandén, researcher at Lund University.

A step towards individualised cancer therapy

“Our discovery can partially explain why immunotherapies have thus far only had limited effects in AML. It’s an important step forward, but continued research and clinical trials will be needed before it can be relevant as a treatment for a patient group that is in great need of new therapies,” said Niklas Landberg, research group leader at Lund University and Medical Registrar in Hematology at Skåne University Hospital.

The study marks real progress towards more individualised cancer therapy, where a patient’s tumour can be targeted based on its unique characteristics and defences. Further development and testing of the antibody will continue, with the ultimate aim of establishing clinical trials in the future.