A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas
Abstract Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-00536-8 |
| _version_ | 1818938986705453056 |
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| author | Lawrence S. Lamb Larisa Pereboeva Samantha Youngblood G. Yancey Gillespie L. Burton Nabors James M. Markert Anindya Dasgupta Catherine Langford H. Trent Spencer |
| author_facet | Lawrence S. Lamb Larisa Pereboeva Samantha Youngblood G. Yancey Gillespie L. Burton Nabors James M. Markert Anindya Dasgupta Catherine Langford H. Trent Spencer |
| author_sort | Lawrence S. Lamb |
| collection | DOAJ |
| description | Abstract Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate lymphocyte effectors such as NK and γδ T cells that recognize NKG2DL is limited by the drug’s concomitant lymphodepleting effects. We have previously shown that modification of γδ T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O6-alkylguanine DNA alkyltransferase (AGT) thereby enabling γδ T cell function in therapeutic concentrations of TMZ. In this study, we tested this strategy which we have termed Drug Resistant Immunotherapy (DRI) to examine whether combination therapy of TMZ and MGMT-modified γδ T cells could improve survival outcomes in four human/mouse xenograft models of primary and refractory GBM. Our results confirm that DRI leverages the innate response of γδ T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach. |
| first_indexed | 2024-12-20T06:16:34Z |
| format | Article |
| id | doaj.art-c28e1cc2e93d4747993b3ae118687a18 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T06:16:34Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c28e1cc2e93d4747993b3ae118687a182022-12-21T19:50:32ZengNature PortfolioScientific Reports2045-23222021-10-011111810.1038/s41598-021-00536-8A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomasLawrence S. Lamb0Larisa Pereboeva1Samantha Youngblood2G. Yancey Gillespie3L. Burton Nabors4James M. Markert5Anindya Dasgupta6Catherine Langford7H. Trent Spencer8Department of Medicine, Division of Hematology and Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology and Oncology, University of Alabama at BirminghamDepartment of Medicine, Division of Hematology and Oncology, University of Alabama at BirminghamDepartment of Neurosurgery, University of Alabama at BirminghamDepartment of Neurology, Division of Neuro-Oncology, University of Alabama at BirminghamDepartment of Neurosurgery, University of Alabama at BirminghamDepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory UniversityDepartment of Neurosurgery, University of Alabama at BirminghamDepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory UniversityAbstract Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate lymphocyte effectors such as NK and γδ T cells that recognize NKG2DL is limited by the drug’s concomitant lymphodepleting effects. We have previously shown that modification of γδ T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O6-alkylguanine DNA alkyltransferase (AGT) thereby enabling γδ T cell function in therapeutic concentrations of TMZ. In this study, we tested this strategy which we have termed Drug Resistant Immunotherapy (DRI) to examine whether combination therapy of TMZ and MGMT-modified γδ T cells could improve survival outcomes in four human/mouse xenograft models of primary and refractory GBM. Our results confirm that DRI leverages the innate response of γδ T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach.https://doi.org/10.1038/s41598-021-00536-8 |
| spellingShingle | Lawrence S. Lamb Larisa Pereboeva Samantha Youngblood G. Yancey Gillespie L. Burton Nabors James M. Markert Anindya Dasgupta Catherine Langford H. Trent Spencer A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas Scientific Reports |
| title | A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas |
| title_full | A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas |
| title_fullStr | A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas |
| title_full_unstemmed | A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas |
| title_short | A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas |
| title_sort | combined treatment regimen of mgmt modified γδ t cells and temozolomide chemotherapy is effective against primary high grade gliomas |
| url | https://doi.org/10.1038/s41598-021-00536-8 |
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