Engineered T cells overexpressing GLUT3 increase their energy and help them improve tumor control
The HI-TIDe’s T cell engineering group expose a promising clinical strategy for improving patient responses to ACT.
In order to improve the efficacy of adoptive T cell transfer (ACT) against cancer it is widely accepted that barriers in the tumor microenvironment must be overcome. Competition from tumor cells for nutrients, including glucose, can impair the effector function and the persistence of adoptively transferred T cells, and can be limiting to responses to immune checkpoint blockade.
Researchers in the T cell engineering group of the Hi-TIDe sought to explore the enforced expression of the high affinity glucose transporter GLUT3 by cytotoxic T lymphocytes (CTLs). They observed enhanced glucose uptake and increased glycogen and fatty acid storage, as well as improved mitochondrial fitness, reduced reactive oxygen species (ROS) levels, higher abundance of the anti-apoptotic protein Mcl-1, and better resistance to stress by the GLUT3-engineered CTLs.
Importantly, the gene-modification also significantly improved the control of B16 melanoma tumors upon ACT and increased mouse survival. Moreover, a proportion of mice treated by GLUT3-T cells were cured and protected from rechallenge. Taking these findings together, researchers conclude that enforcing the expression of GLUT3 by T cells is a promising clinical strategy for improving patient responses to ACT.
This study*, published in Frontiers Immunology, was conducted by Elisabetta Cribioli and led by Hi-TIDe group leader Dr Melita Irving and Pr George Coukos, in collaboration with Pr Christoph Hess of the University Hospital of Basel, Switzerland.
The project was supported by Ludwig Cancer Research, the Swiss National Science Foundation (SNSF/FNS to MI: 310030_204326), the Prostate Cancer Foundation and Cancera.
*Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage
