The tumour microenvironment has long since hindered the capability of adoptive cell therapy in treating solid tumours. Whilst adoptive cell therapy involving allogenic or autologous T cells is a promising approach that has demonstrated remarkable effectiveness in combating haematological malignancies, the efficacy of this approach is limited in solid tumours. This is due to a lack of tumour-specific antigens in addition to an immunosuppressive tumour microenvironment, which prevents T cells from infiltrating into the tumour and results in T cell exhaustion.
Members of the hypoxia-inducible factor (HIF) family have gained recognition as important regulators of T-cell metabolism and function. In this study, the Van den Eynde group, led by the Brussels-based research team, utilise CRISPR-Cas9 technology to delete prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3. This deletion stabilises HIF-1 signalling in CD8 T cells that have already undergone differentiation and activation, modelling the T cell phenotype seen in a clinical setting.
They observed that PHD2/3 deletion significantly enhanced T-cell activation and effector functions, improving the therapeutic responses to adoptive T-cell transfer in a number of tumour models. The effect was found to be dependent on HIF-1α and is accompanied by increased glycolytic flux, holding potential for advancing CD8 T-cell-based therapies and overcoming immune suppression in the tumour microenvironment.
Read the full article in Nature Communications.