RT Journal Article
SR Electronic
T1 Genetically engineering glycolysis in T cells increases their antitumor function
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e008434
DO 10.1136/jitc-2023-008434
VO 12
IS 7
A1 Toledano Zur, Raphaëlle
A1 Atar, Orna
A1 Barliya, Tilda
A1 Hoogi, Shiran
A1 Abramovich, Ifat
A1 Gottlieb, Eyal
A1 Ron-Harel, Noga
A1 Cohen, Cyrille J
YR 2024
UL http://jitc.bmj.com/content/12/7/e008434.abstract
AB Background T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.Methods Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors.Results Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors.Conclusion In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.Data are available upon reasonable request.