More than 90% of cancer deaths are caused by metastasis—when tumour cells break away and colonise other organs—and a team has now identified a biochemical switch inside immune cells that, when turned on, can trigger the body to reject these secondary tumours. This matters because current immunotherapies often fail against established metastases. The researchers discovered that hyperactivating an enzyme called PI3K in helper T cells unleashes a powerful immune attack on lung metastases in mice. The puzzle is that some existing drugs—including aspirin—block PI3K, but this work shows that in certain contexts the pathway must be *activated* to work. The team will dissect the mechanism: which other immune cells the helper T cells recruit, and how to safely boost PI3K activity using available drugs. If successful, this fundamental science could lead to a new class of anti-metastatic therapies. These would aim to prevent dormant cancer cells from ever establishing secondary tumours in patients who have had early-stage cancer treated but remain at risk. The researchers are already comparing their mouse findings with human data from the Add Aspirin trial, bridging the lab to the clinic.
View original technical description
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.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know