Defining non-redundant functions of glycogen synthase kinase (GSK)-3 alpha and GSK-3 beta in T cell subsets that control tumour growth

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Our immune system protects us against numerous, frequent infections. It is now recognised that the immune system also helps to detect and destroy the early stages of cancer. Understanding how the immune system works is key to improving our knowledge of how infections and cancer can be controlled, for example by designing treatments that enhance the action of immune cells.We are interested in a group of white blood cells known as T cells. These cells patrol the tissues and look out for cells that have become infected with viruses or which have become cancerous. On detecting cancer cells, T cells do three things; they kill the cancer cells directly, they release hormone-like molecules called cytokines and chemokines that recruit other types of white blood cell to the site and they help these other immune cells to kill the tumour and prevent its spread. We are interested in these helper cells and how they are regulated. In fact these helper T cells are comprised of several different types, all with differing roles and sites of action. Although the immune system can detect and kill tumours, cancer cells eventually escape the attention of the immune system. They do this by a variety of mechanisms which turn down the activity of the T cells and other immune components. We are interested in an enzyme called GSK-3. This is a molecular switch present in all cells which turns cell activity on and off. We have shown that in cancer, GSK-3 switches off T cells. If we inhibit GSK-3 with drugs then the switch is turned back on and the T cells once again attack the tumour. Our results suggest a strategy to treat cancer. Drugs that switch off GSK-3 might help to boost the patient's immune system and eliminate the cancer. However, we know very little about GSK-3 action and in fact there are two types of GSK-3 in all cells and they do not have exactly the same functions. Furthermore, because GSK-3 is expressed in all tissues, current GSK-3 are not specific to immune cells and can be toxic. In the proposed here we will use cellular and molecular methods coupled with cancer models to understand the action of GSK-3 on helper T cells. By identifying the precise T cell types that are regulated by GSK-3 and by finding other molecules that GSK-3 regulates we hope in the future to be able to design new improved drugs that could be used in patients to eliminate their cancer by activating their immune system.