More than 60,000 people in the UK are diagnosed each year with cancers of the digestive tract, and existing immunotherapies fail many of them. These cancers are difficult to treat because the immune cells called macrophages, which normally protect the gut, can be hijacked to help tumours grow. Current immunotherapies mostly target a different type of immune cell—T-cells—and can cause severe side effects because they act on many cell types at once. The researchers have identified a protein called NRROS that appears to control macrophage behaviour specifically in the brain, but they do not yet know if it does the same in the gut. This project will answer three questions: how NRROS regulates signalling pathways in different digestive-tract tissues, whether it controls gut macrophage function and inflammation, and whether removing NRROS improves outcomes in a mouse model of colon cancer. If NRROS proves to be a macrophage-specific switch in the gut, it could become a target for a new class of immunotherapies that act only on disease-relevant cells. That would offer an alternative for patients who do not respond to T-cell-based treatments or who suffer side effects from less targeted therapies. The findings will be shared with drug developers and clinicians to accelerate progress toward clinical trials.
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Biological immunotherapies have proved an effective way of treating a variety of diseases. Cancer immunotherapies, such as immune checkpoint inhibitors, have offered new and exciting treatment options, rapidly becoming established in clinical practice. However, signalling pathways that contribute to the development of diseases such as cancer are often also used by other cells in the body, making it difficult to treat the diseased cells without causing unwanted side-effects in other cells. Currently available immunotherapies are also not effective in all groups of patients. For these reasons, new and more targeted therapies that are focused on to disease relevant cells are urgently needed. Macrophages are an innate immune cell type found in all organs of the body. Although macrophages usually help to fight infection and maintain healthy organ functions, they have also been shown to play a role in the development of cancers, including those of the digestive tract. In the UK, more than 60,000 people develop cancer affecting their oesophagus, stomach, small intestine or bowel each year, with a 5-year survival rate between 12 and 53%, depending on the affected area. Immunotherapies that target macrophages in these tissues to promote their anti-tumour functions are not yet available but hold exciting potential to expand the repertoire of available therapies for patients which exhibit side-effects in response to untargeted therapies and for patients which don’t respond to conventional immunotherapies that mostly promote anti-tumour functions of adaptive T-cells. We have identified a potential macrophage-specific molecular target, called NRROS, that could be used to develop new therapies for cancers. This molecular target has been shown to regulate macrophages in the brain, but little is currently known about whether it also regulates macrophages in other organs such as the those of the digestive tract. The effects of targeting this molecule to treat cancer are also largely unknown. The aims of this proposal are to study the role of NRROS in regulating the functions of macrophages in tissues of the digestive tract, and to determine whether it could be developed as a new target for the treatment of intestinal cancers. We will achieve our aims by addressing the following three questions: 1) What is the role of NRROS in regulating cancer-relevant signalling pathways in different tissues of the digestive tract and in different types of macrophages? 2) Does NRROS regulate intestinal macrophage functions and inflammatory responses? 3) Does NRROS-deletion improve disease outcome in a model of colon- cancer? We will share our new understanding with other research groups, clinicians, and drug companies interested in cancer drug development, supporting its progress into a new treatment for patients.
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