PHD2/3 deletion in CD8 T cells enhances their effector functions and improves tumor response to adoptive cell therapy
Year: 2024
Type: dissertation
Abstract: Adoptive cell therapy, a promising treatment for hematological malignancies, faces limitations in solid tumors due to the hypoxic and immunosuppressive tumor microenvironment. The transcription factor Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in adaptative response to hypoxia. Here, we aimed to understand the impact of hypoxia and HIF-1α on CD8 T cells with the aim to find new immunotherapy strategies. Using genetic modulations, we deleted or stabilized HIF-1α in CD8 T cells. We observed that HIF-1α stabilization in CD8 T cells led to increased glycolysis, expression of activation markers, and enhanced cytolytic capacity. Furthermore, adoptive transfer of CD8 T cells expressing high levels of HIF-1α resulted in improved tumor control in multiple preclinical models. Finally, stabilization of HIF-1α with the pharmacological inhibitor IOX4 demonstrated potential to enhance the function of human CD8 T cell, offering a promising avenue for improving cancer immunotherapies.
Source: Digital Access to Libraries
Author: Dvorakova, Tereza
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6995834089