Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control.
| Autor: | Johanna I; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands., Hernández-López P; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands., Heijhuurs S; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands., Scheper W; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands., Bongiovanni L; Department of Biomolecular Health Sciences, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., de Bruin A; Department of Biomolecular Health Sciences, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands., Beringer DX; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands., Oostvogels R; Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands., Straetemans T; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.; Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands., Sebestyen Z; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands., Kuball J; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.; Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands. |
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| Jazyk: | angličtina |
| Zdroj: | Frontiers in immunology [Front Immunol] 2021 Oct 25; Vol. 12, pp. 752699. Date of Electronic Publication: 2021 Oct 25 (Print Publication: 2021). |
| DOI: | 10.3389/fimmu.2021.752699 |
| Abstrakt: | γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8 + TEG011. We subsequently explored the concept of additional redirection of CD4 + T cells through co-expression of the human CD8α gene into CD4 + and CD8 + TEG011 cells, later referred as TEG011_CD8α. Adoptive transfer of TEG011_CD8α cells in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mice injected with tumor HLA-A*24:02 + cells showed superior tumor control in comparison to TEG011, and to mock control groups. The total percentage of mice with persisting TEG011_CD8α cells, as well as the total number of TEG011_CD8α cells per mice, was significantly improved over time, mainly due to a dominance of CD4 + CD8 + double-positive TEG011_CD8α, which resulted in higher total counts of functional T cells in spleen and bone marrow. We observed that tumor clearance in the bone marrow of TEG011_CD8α-treated mice associated with better human T cell infiltration, which was not observed in the TEG011-treated group. Overall, introduction of transgenic human CD8α receptor on TEG011 improves antitumor reactivity against HLA-A*24:02 + tumor cells and further enhances in vivo tumor control. Competing Interests: DB, ZS, and JK are inventors on different patents with γδTCR sequences, recognition mechanisms, and isolation strategies. JK is cofounder and shareholder of Gadeta (www.gadeta.nl). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Johanna, Hernández-López, Heijhuurs, Scheper, Bongiovanni, de Bruin, Beringer, Oostvogels, Straetemans, Sebestyen and Kuball.) |
| Databáze: | MEDLINE |
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