Genetically Engineering Glycolysis in T Cells Increases Their Antitumor Function

Authors

Raphaëlle Toledano Zur
Orna Atar
Tilda Barliya
Shiran Hoogi
Ifat Abramovich
Eyal Gottlieb
Noga Ron-Harel
Cyrille J Cohen

Publication Date

7-4-2024

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

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.

Keywords

Humans, Glycolysis, Animals, T-Lymphocytes, Mice, Genetic Engineering, Tumor Microenvironment, Cell Line, Tumor, Neoplasms, Xenograft Model Antitumor Assays

Comments

Supplementary Materials

PMID: 38964783