Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control
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 re...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.752699/full |
| _version_ | 1823967517251469312 |
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| author | Inez Johanna Patricia Hernández-López Sabine Heijhuurs Wouter Scheper Laura Bongiovanni Alain de Bruin Alain de Bruin Dennis X. Beringer Rimke Oostvogels Trudy Straetemans Trudy Straetemans Zsolt Sebestyen Jürgen Kuball Jürgen Kuball |
| author_facet | Inez Johanna Patricia Hernández-López Sabine Heijhuurs Wouter Scheper Laura Bongiovanni Alain de Bruin Alain de Bruin Dennis X. Beringer Rimke Oostvogels Trudy Straetemans Trudy Straetemans Zsolt Sebestyen Jürgen Kuball Jürgen Kuball |
| author_sort | Inez Johanna |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T18:28:20Z |
| format | Article |
| id | doaj.art-e17f0e99771741b296928ed52e569024 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T18:28:20Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e17f0e99771741b296928ed52e5690242022-12-21T21:37:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.752699752699Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor ControlInez Johanna0Patricia Hernández-López1Sabine Heijhuurs2Wouter Scheper3Laura Bongiovanni4Alain de Bruin5Alain de Bruin6Dennis X. Beringer7Rimke Oostvogels8Trudy Straetemans9Trudy Straetemans10Zsolt Sebestyen11Jürgen Kuball12Jürgen Kuball13Center for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Biomolecular Health Sciences, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsDepartment of Biomolecular Health Sciences, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsDepartment of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Hematology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Hematology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsCenter for Translational Immunology, University Medical Center Utrecht, Utrecht, NetherlandsDepartment of Hematology, University Medical Center Utrecht, Utrecht, NetherlandsγδT 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.752699/fullcancer immunotherapyTEGsmouse modelpreclinical (in vivo) studiesTCR engineeringhuman leukocyte antigens (HLA) |
| spellingShingle | Inez Johanna Patricia Hernández-López Sabine Heijhuurs Wouter Scheper Laura Bongiovanni Alain de Bruin Alain de Bruin Dennis X. Beringer Rimke Oostvogels Trudy Straetemans Trudy Straetemans Zsolt Sebestyen Jürgen Kuball Jürgen Kuball Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control Frontiers in Immunology cancer immunotherapy TEGs mouse model preclinical (in vivo) studies TCR engineering human leukocyte antigens (HLA) |
| title | Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control |
| title_full | Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control |
| title_fullStr | Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control |
| title_full_unstemmed | Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control |
| title_short | Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control |
| title_sort | adding help to an hla a 24 02 tumor reactive γδtcr increases tumor control |
| topic | cancer immunotherapy TEGs mouse model preclinical (in vivo) studies TCR engineering human leukocyte antigens (HLA) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.752699/full |
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