TY - JOUR

T1 - Glycolysis inhibition affects proliferation and cytotoxicity of Vγ9Vδ2 T cells expanded for adoptive cell therapy

AU - Aehnlich, Pia

AU - Santiago, Marta Velasco

AU - Dam, Søren Helweg

AU - Saló, Sara Fresnillo

AU - Rahbech, Anne

AU - Olsen, Lars Rønn

AU - thor Straten, Per

AU - Desler, Claus

AU - Holmen Olofsson, Gitte

N1 - Publisher Copyright: © 2024 International Society for Cell & Gene Therapy

PY - 2024

Y1 - 2024

N2 - Background aims: Vγ9Vδ2 T cells are under investigation as alternative effector cells for adoptive cell therapy (ACT) in cancer. Despite promising in vitro results, anti-tumor efficacies in early clinical studies have been lower than expected, which could be ascribed to the complex interplay of tumor and immune cell metabolism competing for the same nutrients in the tumor microenvironment. Methods: To contribute to the scarce knowledge regarding gamma delta T-cell metabolism, we investigated the metabolic phenotype of 25-day-expanded Vγ9Vδ2 T cells and how it is intertwined with functionality. Results: We found that Vγ9Vδ2 T cells displayed a quiescent metabolism, utilizing both glycolysis and oxidative phosphorylation (OXPHOS) for energy production, as measured in Seahorse assays. Upon T-cell receptor activation, both pathways were upregulated, and inhibition with metabolic inhibitors showed that Vγ9Vδ2 T cells were dependent on glycolysis and the pentose phosphate pathway for proliferation. The dependency on glucose for proliferation was confirmed in glucose-free conditions. Cytotoxicity against malignant melanoma was reduced by glycolysis inhibition but not OXPHOS inhibition. Conclusions: These findings lay the groundwork for further studies on manipulation of Vγ9Vδ2 T-cell metabolism for improved ACT outcome.

AB - Background aims: Vγ9Vδ2 T cells are under investigation as alternative effector cells for adoptive cell therapy (ACT) in cancer. Despite promising in vitro results, anti-tumor efficacies in early clinical studies have been lower than expected, which could be ascribed to the complex interplay of tumor and immune cell metabolism competing for the same nutrients in the tumor microenvironment. Methods: To contribute to the scarce knowledge regarding gamma delta T-cell metabolism, we investigated the metabolic phenotype of 25-day-expanded Vγ9Vδ2 T cells and how it is intertwined with functionality. Results: We found that Vγ9Vδ2 T cells displayed a quiescent metabolism, utilizing both glycolysis and oxidative phosphorylation (OXPHOS) for energy production, as measured in Seahorse assays. Upon T-cell receptor activation, both pathways were upregulated, and inhibition with metabolic inhibitors showed that Vγ9Vδ2 T cells were dependent on glycolysis and the pentose phosphate pathway for proliferation. The dependency on glucose for proliferation was confirmed in glucose-free conditions. Cytotoxicity against malignant melanoma was reduced by glycolysis inhibition but not OXPHOS inhibition. Conclusions: These findings lay the groundwork for further studies on manipulation of Vγ9Vδ2 T-cell metabolism for improved ACT outcome.

KW - adoptive cell therapy

KW - cytotoxicity

KW - glycolysis

KW - metabolism

KW - Vγ9Vδ2 T cells

KW - γδ T cells

UR - http://www.scopus.com/inward/record.url?scp=85193640413&partnerID=8YFLogxK

U2 - 10.1016/j.jcyt.2024.04.072

DO - 10.1016/j.jcyt.2024.04.072

M3 - Journal article

C2 - 38775775

AN - SCOPUS:85193640413

JO - Cytotherapy

JF - Cytotherapy

SN - 1465-3249

ER -