Grant: Operating Grant

Our immune system can eliminate cancer as it develops. However, due to reasons not fully understood, some cancers develop ways to avoid elimination by 'killer' cells of our immune system called natural killer or NK cells (immune escape). As tumours grow, their supply of oxygen can't adequately reach all layers of the rapidly increasing tumour cell population. Consequently, tumours develop poorly oxygenated or hypoxic regions. We hypothesize that hypoxia contributes to immune escape in cancer. We have already shown that when tumour cells are exposed to hypoxia they shed a protein (MICA) that normally flags them for elimination by NK cells. We now propose to characterise in detail the mechanism responsible for the shedding of MICA from tumour cells when they are exposed to hypoxia, as this mechanism is also responsible for immune escape. When cancer cells are exposed to severe hypoxia they can't produce the molecule nitric oxide (NO). We showed that when NO is not produced, as when the oxygen supply is limited, tumour cells acquire aggressive properties such as increased ability to spread and increased resistance to anti-cancer drugs. We recently discovered that the ability of tumour cells to shed MICA and evade destruction by NK cells when exposed to hypoxia is also due to decreased NO production. This is a key finding because we can now interfere with the effect of hypoxia on immune escape by introducing NO activity in the form of drugs that release or mimic NO. Our proposed studies will determine which step of the mechanism of immune escape NO regulates. To reach our goals, we will use cell culture and animal models, as well as pharmacological, biochemical, immunological, and molecular methods. The outcomes will increase our understanding of how cancers evade immune destruction and will likely have translational value, as re-introduction of NO activity in cancer cells may be used to enhance immunotherapy, or may even be an effective 'stand-alone' therapy.