Understanding CD8 T cell function under the tumour environment condition hypoxia




Townsend, Katelin N.

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As CD8 T cells migrate to tumour sites, they experience conditions of low oxygen or hypoxia, in the tumour environment. Hypoxia results due to the rapid proliferation of tumour cells which deplete essential nutrients such as oxygen as they expand beyond normal vasculature. Hypoxia can cause attenuated immune responses due to the resultant signalling events and metabolic changes initiated in CD8 T cells under these conditions. CD8 T cells are important mediators of anti-tumour activity as they directly kill tumour cells, and are associated with increased survival outcomes in cancer patients. Therefore, I sought to determine the impact of low oxygen on CD8 T cell function. In addition, I investigated the role for autophagy, a cell survival process induced by nutrient depletion, in T cells under hypoxia. The first chapter of this thesis outlines the effects of the hypoxic tumour environment and the known roles for autophagy in T cells. In the second chapter, the role of hypoxia and hypoxia-induced autophagy will be explored in CD8 T cells and the impact on cell function assessed using a transgenic mouse model. The importance of hypoxia for T cell activity clinically will be examined in Chapter 3. High-grade serous ovarian tumours will be evaluated for their oxygenation levels and immune status and correlations with patient survival will be assessed. These results are important for understanding how CD8 T cells function during pathophysiological oxygen conditions found in tumours and reveal hypoxia as a new relevant inducer of autophagy in T cells. Ultimately, these results highlight the need for further research discoveries which promote T cell function during conditions of low oxygen in tumours. Such future discoveries may be combined with therapies which boost or enhance immune responses, allowing more optimal tumour treatments to improve patient survival.



Immunology, Cancer, Hypoxia, Autophagy