Genetically engineering glycolysis in T cells increases their antitumor function

• Published in: Journal for immunotherapy of cancer Vol. 12; no. 7; p. e008434
• Main Authors: Toledano Zur, Raphaëlle, Atar, Orna, Barliya, Tilda, Hoogi, Shiran, Abramovich, Ifat, Gottlieb, Eyal, Ron-Harel, Noga, Cohen, Cyrille J
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 04-07-2024; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Acidification; Animals; Antigens; Cell Line, Tumor; Cells; Cytokines; Cytotoxicity; Enzymes; Flow cytometry; Genetic Engineering; Glucose; Glycolysis; Humans; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy; Lymphocytes; Melanoma; Metabolism; Metabolites; Mice; Neoplasms - immunology; Neoplasms - metabolism; Receptors, Antigen; Respiration; T-Lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Microenvironment; Tumor necrosis factor-TNF; Tumors; Xenograft Model Antitumor Assays; United States > US; Israel; California; T-Lymphocytes; Receptors, Antigen; Immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008434

BackgroundT 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.MethodsHerein, 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.ResultsEngineered 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.ConclusionIn summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.