Transgelin 2 guards T cell lipid metabolism and antitumour function

Abstract

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of Tcells by extracellular fatty acids(1-3). Fatty-acid-binding protein5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8(+) Tcells(4,5). However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8(+) Tcells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8(+) Tcells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8(+) Tcells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8(+) Tcells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor Tcells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in Tcell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.