A promising strategy to enhance the effectiveness of cancer immunotherapy

In cancer immunotherapy, the body’s immune system is empowered to fight cancer. Various ways are used to achieve this. One approach, called adoptive T cell therapy, involves growing T cells (the immune cells that can kill cancer cells) in the lab, and then injecting these cells in the patient. The therapy has demonstrated remarkable effectiveness in combating haematological malignancies, but the efficacy is limited in solid tumours. This is thought to be due to the microenvironment in the tumour, which prevents the T cells from infiltrating and makes them powerless.

The lab of Benoit Van den Eynde proposes an innovative strategy for adoptive T cell therapy in solid tumors. They demonstrated that this approach significantly improves the survival and efficacy of the T cells in inhibiting tumor growth in mouse models. It is effective across a range of tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. This new approach holds the potential to significantly elevate the therapeutic outcomes of adoptive T cell therapy.

The approach involves the genetic or pharmacological activation of the HIF-1α pathway in T cells that are activated before their infusion into patients. The HIF (hypoxia-inducible factor) pathway is important for cells under hypoxic conditions (shortage of oxygen), enabling them to continue highly energy-dependent processes. In recent years, members of the HIF family have gained recognition as important regulators of T-cell metabolism and function.

The researchers utilized 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.

Article describing this research

Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells

Dvorakova T, Finisguerra V, Formenti M, Loriot A, Boudhan L, Zhu J, Van den Eynde BJ

Nat Commun 2024, 15(1):7789