Centre scientists help identify novel immune system mechanism with potential to aid checkpoint blocking cancer therapies

Scientists at the Centre for Cancer Immunology have been involved in a new study, with researchers at the Universities of Liverpool and Aberdeen, which has gained new insight into a previously unknown aspect of the immune system that could help improve cancer treatment.

CTLA-4 is a cell surface molecule that plays a crucial role in the immune system. It is a so-called “checkpoint” receptor responsible for maintaining immune balance and tolerance and works to prevent the immune system becoming too active at the end of a normal immune response. However, it is also subverted by cancer cells to prevent the immune system from attacking them.

Therefore, scientists developed antibodies targeting CTLA-4 and these have shown promise in treating various cancers. However, the exact mechanisms behind their anti-tumour effects have remained elusive and there are issues with immune toxicity.

The new work sheds light on this and reveals there is also an overlooked form of CTLA4, that is released from the cell, known as soluble CTLA-4 (sCTLA-4). The research team investigated sCTLA-4’s potential impact on cancer immunotherapy and explored the functional properties of sCTLA-4 and tested the effectiveness of a specific antibody targeting sCTLA-4.

In the study, published in Molecular Therapy, they found that tumours expressing sCTLA-4 inhibited the activity of cytotoxic cancer-killing T-cells leading to the cancer growing and spreading more rapidly.

However, when the researchers blocked sCTLA-4 with a specific antibody, this suppression was reversed, and the T-cells were able to find and attack the cancer.

Professor Mark Cragg, from the University of Southampton, said: “This research, pioneered by Frank Ward and Lekh Dahal sheds new light on the previously unknown role of sCTLA-4 and emphasises the need for a comprehensive understanding of the various forms of immune checkpoint receptors. If we can better understand which forms are responsible for anti-tumour activity versus toxicity then it could allow us to provide a more nuanced, less toxic and effective approach to treatment.”