Grant: Project Grant

Type I interferons (IFN-Is) are key molecular signals that tell the immune system to turn on its defences against invading pathogens. The body has several sensors that can trigger the production of type I interferons. One of the most ancient sensors is the stimulator of interferon genes (STING), an intracellular sensor that can detect DNA in the cytosol of cells. Normal cells have their DNA in the nucleus and mitochondria, but if a cell is infected or damaged, such as occurs in cancer, DNA can be released into the cell cytosol- a signal that something is wrong. This in turn causes the STING pathway to produce IFN-Is to wake up the immune system to fight the infection or cancer. Recently, scientists have made synthetic molecules that stimulate STING, referred to as STING agonists. The idea is to use these small molecules for an immune system boost to release IFN-Is to improve immune responses to the cancer. STING agonists have shown great promise in mouse models of melanoma and other cancers. Several are in human clinical trials. This therapy involves several kinds of immune cells, including dendritic cells, T cells, and monocytes, that work together to eliminate the cancer cells. In our study, we are focusing on how STING agonists turn on monocytes in the tumor, which in turn allows them to activate another cell type, the T cells, to eliminate the cancer cells. We are studying how the T cells can be activated by the monocytes to kill tumors as well as prevent cancer recurrence. In human cancer, STING agonists alone may not be enough to trigger tumor regression, but they might be useful to wake up the immune system to allow it to work in concert with new immunotherapeutics, called checkpoint inhibitors, which turn off the brakes on the immune system. To determine the best way to use these approaches in humans, it is important to understand the key cells and processes involved. We will be investigating this approach in mouse models of melanoma.