Cytotoxic T cells depend on the HIF transcription factor for differentiation and effector function. Drops in oxygen potentiate changes in CD8+ T cells via both direct transcriptional effects mediated by HIF, and via epigenetic shifts activated by metabolites including 2-hydroxyglutarate. We are currently investigating the mechanisms underlying these changes, and want to use these insights to improve the effectiveness and persistence of immunotherapy.
We have shown that the myeloid lineages, and in particular macrophage, suppress T cell proliferation in a HIF-dependent manner in hypoxia. This occurs in large part due to the role of HIF in regulating nitric oxide (NO) homeostasis in hypoxia in macrophages. The NO produced has an immunosuppressive role, and we are investigating how to modulate that to potentiate T cell function in hypoxic settings such as tumours.