αβ-T cell receptor transduction gives superior mitochondrial function to γδ-T cells with promising persistence

Mikiya Ishihara; Hiroshi Miwa; Hiroshi Fujiwara; Yasushi Akahori; Takuma Kato; Yoshimasa Tanaka; Isao Tawara; Hiroshi Shiku

doi:10.1016/j.isci.2023.107802

αβ-T cell receptor transduction gives superior mitochondrial function to γδ-T cells with promising persistence

iScience. 2023 Aug 31;26(10):107802. doi: 10.1016/j.isci.2023.107802. eCollection 2023 Oct 20.

Authors

Mikiya Ishihara¹, Hiroshi Miwa², Hiroshi Fujiwara², Yasushi Akahori², Takuma Kato³, Yoshimasa Tanaka⁴, Isao Tawara⁵, Hiroshi Shiku²

Affiliations

¹ Department of Medical Oncology, Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
² Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan.
³ Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
⁴ Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
⁵ Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

Abstract

Adoptive cell therapy using allogeneic γδ-T cells is a promising option for off-the-shelf T cell products with a low risk of graft-versus-host disease (GVHD). Long-term persistence may boost the clinical development of γδ-T cell products. In this study, we found that genetically modified Vγ9⁺Vδ2⁺ T cells expressing a tumor antigen-specific αβ-TCR and CD8 coreceptor (GMC) showed target-specific killing and excellent persistence. To determine the mechanisms underlying these promising effects, we investigated metabolic characteristics. Cytokine secretion by γδ-TCR-stimulated nongene-modified γδ-T cells (NGMCs) and αβ-TCR-stimulated GMCs was equally suppressed by a glycolysis inhibitor, although the cytokine secretion of αβ-TCR-stimulated GMCs was more strongly inhibited by ATP synthase inhibitors than that of γδ-TCR-stimulated NGMCs. Metabolomic and transcriptomic analyses, flow cytometry analysis using mitochondria-labeling dyes and extracellular flux analysis consistently suggest that αβ-TCR-transduced γδ-T cells acquire superior mitochondrial function. In conclusion, αβ-TCR-transduced γδ-T cells acquire superior mitochondrial function with promising persistence.

Keywords: Cellular therapy; Immunology; Molecular biology.