Regulation of innate immune signalling by hypoxia

Innate immunity is the first line of defence against invading pathogens and is also required for the initiation of adaptive immunity. Innate immune responses and inflammation are stimulated by pattern recognition receptors and cytokine receptors. A well-functioning immune defence is crucial for clearance of invading pathogens, but the knowledge of how the immune system is influenced by microenvironmental cues such as hypoxia is still limited. Hypoxia is a common feature in inflammatory sites as well as in solid tumours. In this thesis, I describe a mechanism that hypoxia suppresses immune signalling by receptors such as TNFR1, NOD2, IL-1R and IFN-γR2 that are encoded by uORF-containing mRNAs. This finding unveils an immunological mechanism for desensitisation by hypoxia. The mechanism may be applicable to different physiological or pathophysiological processes, such as autoimmune diseases and cancer. In this thesis, I describe how this mechanism affects tumour immune evasion. Specifically, hypoxic-inhibition of TNF and IFN-γ signalling results in suppression of MHC-I expression levels on the cell surface, which are essential for activation of CD8 T cell dependent anti-tumour immunity. Genetic deletion of uORFs in TNFRSF1A and IFNGR2 counteracts hypoxic inhibition of the expression of MHC-I induced by TNF and IFN-γ in Yumm1.7 mouse melanoma cells, leading to enhanced CD8 T cell-dependent anti-tumour immunity in this syngeneic mouse model. Consistently, higher TNF and IFN-γ signatures predict better clinical outcomes and tumour hypoxia negatively correlates with T cells infiltration and disease specific survival rates in melanoma patients. These data indicate that targeting uORFs counteracts hypoxia-mediated immune suppression in cancer. The finding of oxygen level regulating immune signalling activity may contribute to our understanding of inflammation regulation and development of therapeutics against cancer.