GLUT5 armouring enhances adoptive T cell therapy anti-tumour activity under glucose-limiting conditions

Abstract

Cancer immunotherapy with engineered T cells has become a standard treatment for certain hematologic cancers. However, clinical trial outcomes for solid tumours are significantly lagging. A primary challenge in solid tumours is the lack of essential metabolites in the tumour microenvironment, such as glucose, due to poor vascularization and competition with tumour cells. To address this, we modified T cells to use fructose as an alternative energy source by introducing ectopic GLUT5 expression. We show that "GLUT5-armored" T cells, engineered with either chimeric antigen receptors (CARs) or an ectopic T cell receptor (TCR), achieve enhanced anti-tumour activity in low-glucose environments in both in vitro and in vivo models. This straightforward modification is compatible with current clinical approaches and may improve the efficacy of T cell therapies for solid tumours. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/633365v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@15e10e0org.highwire.dtl.DTLVardef@a5f029org.highwire.dtl.DTLVardef@3a32daorg.highwire.dtl.DTLVardef@e09ff9_HPS_FORMAT_FIGEXP M_FIG C_FIG