The harsh, oxygen-starved microenvironment of solid tumors can pose an insurmountable challenge to antitumor immunity and immunotherapy, often pushing T cells of the immune system into a dysfunctional state known as exhaustion and inhibiting T cell infiltration (see image). Researchers led by Ludwig Institute’s Jingjing Zhu and Benoît Van den Eynde explored how the stabilization of the cellular oxygen sensor—hypoxia inducible factor (HIF)—would affect the antitumor activity of T cells used for adoptive cell therapy (ACT) in mouse models of cancer. The HIFs, which switch on a host of genes that help cells adapt to oxygen starvation, are known to play an important role in regulating T cell metabolism and function. Jingjing, Benoît and colleagues reported in a September issue of Nature Communications that activated tumor-targeting T cells used for ACT were far more effective when genes encoding PHD2 and PHD3, enzymes that help degrade HIF to regulate the hypoxic response, were selectively deleted using CRISPR-Cas9 gene editing. This selective deletion stabilizes HIF-1α signaling and boosts glycolysis, a metabolic process for harvesting energy from sugar that is critical to the function of activated T cells. When used for ACT, T cells lacking PHD2/3 induced potent therapeutic responses against several mouse models of cancer, including those that typically resist immunotherapy. The findings suggest new strategies to improve the efficacy and applicability of ACT for cancer therapy.
Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells
Nature Communications, 2024 September 6