Glycolysis inhibition affects proliferation and cytotoxicity of Vγ9Vδ2 T cells expanded for adoptive cell therapy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cytotherapy |
| ISSN | 1465-3249 |
| DOI | |
| Status | E-pub ahead of print - 2024 |
Bibliografisk note
Funding Information:
This study was supported by the Danish Cancer Society (grant no. R72-A4396-13-S2), Aase og Ejnar Danielsens Fond, Dagmar Marshalls Fond, Axel Muusfeldts Fond, Else og Mogens Wedell Wedellsborg Fond, AP M\u00F8ller Fonden, KV Fonden, Den B\u00F8hmske Fond, and the Independent Research Fund Denmark (grant no. 8020-00005B). PA received partial Ph.D. stipends from the Clinical Academic Group in Translational Hematology, part of Greater Copenhagen Health Science Partners, and the Department of Immunology and Microbiology, University of Copenhagen. MVS was supported by a scholarship of the Danish Cancer Society.
Funding Information:
This study was supported by the Danish Cancer Society (grant no. R72-A4396-13-S2), Aase og Ejnar Danielsens Fond, Dagmar Marshalls Fond, Axel Muusfeldts Fond, Else og Mogens Wedell Wedellsborg Fond, AP M\u00F8ller Fonden, KV Fonden, Den B\u00F8hmske Fond and Independent Research Fund Denmark (grant no. 8020-00005B). PA received partial PhD stipends from the Clinical Academic Group in Translational Hematology (part of Greater Copenhagen Health Science Partners) and the Department of Immunology and Microbiology, University of Copenhagen. MVS was supported by a scholarship from the Danish Cancer Society. Conception and design of the study: PA, PtS, CD, GHO. Acquisition of data: PA, MVS, SFS, AR. Analysis and interpretation of data: All authors contributed. Drafting the manuscript: PA. Revising the manuscript: MVS, SHD, PtS, CD, GHO. All authors have approved the final article. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Publisher Copyright:
© 2024 International Society for Cell & Gene Therapy
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