Enhancing T cell immunity to cancer metastasis

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Metastatic cancer results from the escape of individual cells from the primary tumour to distal parts of the body. The process of cancer metastasis is responsible for more than 90% of cancer deaths. One example is the skin cancer melanoma from which cells can become dislodged and travel to the liver or lung. In this proposal, we have identified a biochemical pathway within T cells which when activated, promotes extremely potent immune-mediated rejection of lung metastases. The biochemical pathway is activated by an enzyme called PI3K. There are several drugs used in the clinic that inhibit this pathway and some of these have been used to stimulate the immune system. Here we propose circumstances where the pathway instead needs to be activated. The aims of this proposal are to understand how hyperactivation of PI3K leads to the elimination of cancer metastases and to exploit this knowledge to improve immunity to cancer metastases. Our work is organised into two Aims:Aim 1 will find out the mechanism of helper T cell-mediated elimination of lung tumours. We will determine what other immune subtypes the helper T cells engage in the fight against cancer.Aim 2 explores a novel biochemical pathway we have discovered that can unleash potent PI3K activity in T cells using available drugs such as aspirin.This research is mainly focused on the use of preclinical mouse models to establish the underlying mechanisms of the remarkable anti-metastatic tumour responses we have uncovered. These data will be compared to primary human data from cancer patients through our collaborative links with the Add Aspirin trial (http://www.addaspirintrial.org/). This research will enable development of a new generation of anti-metastatic immune-based therapies which aim to prevent successful development of metastases in patients who have been diagnosed and treated with early cancer but who are at risk of metastasis.