Grant: Operating Grant

Our immune system can eliminate cancer as it develops. Cells from our innate immune system destroy tumour cells on first contact without having to be primed, whereas cells from our adaptive immune system recognise and destroy cancer cells after being primed and undergoing expansion. For reasons not well understood, some cancers develop ways to avoid elimination by our immune system. This is referred to as 'immune escape'. As tumours grow, their supply of oxygen can't adequately reach all layers of cancer cells. Consequently, tumours develop poorly oxygenated or 'hypoxic' regions. We have already shown that when tumour cells are exposed to hypoxia they become resistant to destruction by cells of our innate immune system. We now propose that hypoxia also contributes to the ability of cancer cells to avoid destruction by our adaptive immune system and have evidence that it may be possible to interfere with this mechanism of immune escape in cancer. We have preliminary results in support of this hypothesis. When cancer cells become severely hypoxic they can't produce the molecule nitric oxide (NO). We showed that when NO is not produced, tumour cells are better able to spread, to resist chemotherapy and to evade destruction by our innate immune system. We now propose that a lack of NO production by tumour cells underlies the mechanism of hypoxia-induced resistance to adaptive immunity. Our studies will examine this concept. Furthermore, we should be able to interfere with immune escape by introducing NO activity in the form of drugs that release or mimic NO. To reach our goals, we will use cell culture and animal models, as well as pharmacological, biochemical, immunological, and molecular tools. The outcomes will increase our knowledge of how cancers evade immune destruction and will 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.