Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma
Chimeric antigen receptor T-cell (CAR-T) therapies have shown promise in glioblastoma clinical studies, but responses remain inconsistent due to heterogeneous tumor antigen expression and immune evasion post-treatment. NKG2D CAR-T cells have demonstrated a favorable safety profile in patients with h...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1519777/full |
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| author | Junchen Liu Junchen Liu Kun Dai Kun Dai Muhammad Auwal Saliu Muhammad Auwal Saliu Mansur Dabai Salisu Mansur Dabai Salisu Jiangyu Gan Lukman Olalekan Afolabi Dehong Yan Guizhong Zhang Maoxuan Liu Maoxuan Liu Xiaochun Wan Xiaochun Wan |
| author_facet | Junchen Liu Junchen Liu Kun Dai Kun Dai Muhammad Auwal Saliu Muhammad Auwal Saliu Mansur Dabai Salisu Mansur Dabai Salisu Jiangyu Gan Lukman Olalekan Afolabi Dehong Yan Guizhong Zhang Maoxuan Liu Maoxuan Liu Xiaochun Wan Xiaochun Wan |
| author_sort | Junchen Liu |
| collection | DOAJ |
| description | Chimeric antigen receptor T-cell (CAR-T) therapies have shown promise in glioblastoma clinical studies, but responses remain inconsistent due to heterogeneous tumor antigen expression and immune evasion post-treatment. NKG2D CAR-T cells have demonstrated a favorable safety profile in patients with hematologic tumors, and showed robust antitumor efficacy in various xenograft models, including glioblastoma. However, malignant glioma cells evade immunological surveillance by reducing NKG2D ligands expression or cleavage. To enhance the effectiveness of NKG2D CAR-T therapy, we investigated the potential of combining NKG2D CAR-T with approved drugs that cross the blood-brain barrier and augment NKG2D ligands expression in glioma cells. We found that sodium valproate (VPA), an antiepileptic drug, significantly increased surface NKG2D ligands expression on glioblastoma cells at a sublethal concentration. VPA treatment enhanced the susceptibility of glioblastoma cells to NKG2D CAR-T mediated cytotoxicity in both 2D monolayer and 3D tumor spheroid models in vitro. Moreover, VPA-treated glioblastoma cells stimulated CAR-T cells to produce higher levels of inflammatory cytokines (IL-2, IFN-γ, and IL-6). Mechanistically, VPA upregulated NKG2D ligands expression via the PI3K/Akt signaling pathway. Additionally, VPA treatment augmented the antitumor activity of NKG2D CAR-T cells in a glioblastoma xenograft model in vivo. These preclinical results suggest that combining VPA with NKG2D CAR-T therapy represents a promising strategy for improving glioblastoma treatment, warranting further clinical investigation. |
| format | Article |
| id | doaj-art-f575429b49e240a9b5802677f1b75d9b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-f575429b49e240a9b5802677f1b75d9b2025-01-14T06:10:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15197771519777Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastomaJunchen Liu0Junchen Liu1Kun Dai2Kun Dai3Muhammad Auwal Saliu4Muhammad Auwal Saliu5Mansur Dabai Salisu6Mansur Dabai Salisu7Jiangyu Gan8Lukman Olalekan Afolabi9Dehong Yan10Guizhong Zhang11Maoxuan Liu12Maoxuan Liu13Xiaochun Wan14Xiaochun Wan15Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaInspection Department, Ji’an Central People’s Hospital, Ji’an, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaDepartment of Pediatrics, Indiana University School of Medicine, South Bend, IN, United StatesGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaChimeric antigen receptor T-cell (CAR-T) therapies have shown promise in glioblastoma clinical studies, but responses remain inconsistent due to heterogeneous tumor antigen expression and immune evasion post-treatment. NKG2D CAR-T cells have demonstrated a favorable safety profile in patients with hematologic tumors, and showed robust antitumor efficacy in various xenograft models, including glioblastoma. However, malignant glioma cells evade immunological surveillance by reducing NKG2D ligands expression or cleavage. To enhance the effectiveness of NKG2D CAR-T therapy, we investigated the potential of combining NKG2D CAR-T with approved drugs that cross the blood-brain barrier and augment NKG2D ligands expression in glioma cells. We found that sodium valproate (VPA), an antiepileptic drug, significantly increased surface NKG2D ligands expression on glioblastoma cells at a sublethal concentration. VPA treatment enhanced the susceptibility of glioblastoma cells to NKG2D CAR-T mediated cytotoxicity in both 2D monolayer and 3D tumor spheroid models in vitro. Moreover, VPA-treated glioblastoma cells stimulated CAR-T cells to produce higher levels of inflammatory cytokines (IL-2, IFN-γ, and IL-6). Mechanistically, VPA upregulated NKG2D ligands expression via the PI3K/Akt signaling pathway. Additionally, VPA treatment augmented the antitumor activity of NKG2D CAR-T cells in a glioblastoma xenograft model in vivo. These preclinical results suggest that combining VPA with NKG2D CAR-T therapy represents a promising strategy for improving glioblastoma treatment, warranting further clinical investigation.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1519777/fullCAR-TglioblastomaNKG2Dsodium valproatecombination therapy |
| spellingShingle | Junchen Liu Junchen Liu Kun Dai Kun Dai Muhammad Auwal Saliu Muhammad Auwal Saliu Mansur Dabai Salisu Mansur Dabai Salisu Jiangyu Gan Lukman Olalekan Afolabi Dehong Yan Guizhong Zhang Maoxuan Liu Maoxuan Liu Xiaochun Wan Xiaochun Wan Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma Frontiers in Immunology CAR-T glioblastoma NKG2D sodium valproate combination therapy |
| title | Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma |
| title_full | Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma |
| title_fullStr | Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma |
| title_full_unstemmed | Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma |
| title_short | Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma |
| title_sort | sodium valproate enhances efficacy of nkg2d car t cells against glioblastoma |
| topic | CAR-T glioblastoma NKG2D sodium valproate combination therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1519777/full |
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