Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells
Abstract High grade gliomas (HGG) are incurable brain cancers, where inevitable disease recurrence is driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) chemotherapy, amidst weak immune and natural killer (NK) ce...
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BMC
2025-03-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-01984-3 |
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| author | Brian Meehan Lata Adnani Xianbing Zhu Nadim Tawil Delphine Garnier Ichiro Nakano Sidong Huang Janusz Rak |
| author_facet | Brian Meehan Lata Adnani Xianbing Zhu Nadim Tawil Delphine Garnier Ichiro Nakano Sidong Huang Janusz Rak |
| author_sort | Brian Meehan |
| collection | DOAJ |
| description | Abstract High grade gliomas (HGG) are incurable brain cancers, where inevitable disease recurrence is driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) chemotherapy, amidst weak immune and natural killer (NK) cell surveillance. The present study was designed to understand how to enhance the contribution of innate immunity to post TMZ disease control. Strikingly, molecular subtypes of HGG impacted the repertoire of NK cell sensitivity markers across human HGG transcriptomes, and in a panel of GSCs with either proneural (PN-GSC) or mesenchymal (MES-GSC) phenotypes. Indeed, only MES-GSCs (but not PN-GSCs) were enriched for NK cell ligands and sensitive to NK-mediated cytotoxicity in vitro. While NK cells alone had no effect on HGG progression in vivo, the post-chemotherapy (TMZ) recurrence of MES-GSC-driven xenografts was aborted by timed intracranial injection of live or irradiated NK (NK92MI) cells, resulting in long term survival of animals. This curative effect declined when NK cell administration was delayed relative to TMZ exposure pointing to limits of the immune control over resurging residual tumour stem cell populations that survived chemotherapy. Overall, these results suggest that chemotherapy-dependent tumour depopulation may create a unique window of opportunity for NK-mediated intervention with curative effects restricted to a subset of HGGs driven by mesenchymal brain tumour initiating cells. |
| format | Article |
| id | doaj-art-a161c45bc6f940868bca826752b57d65 |
| institution | DOAJ |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-a161c45bc6f940868bca826752b57d652025-08-20T02:41:36ZengBMCActa Neuropathologica Communications2051-59602025-03-0113111710.1186/s40478-025-01984-3Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cellsBrian Meehan0Lata Adnani1Xianbing Zhu2Nadim Tawil3Delphine Garnier4Ichiro Nakano5Sidong Huang6Janusz Rak7Research Institute of the McGill University Health CentreResearch Institute of the McGill University Health CentreGoodman Cancer Institute, McGill UniversityResearch Institute of the McGill University Health CentreSorbonne UniversityDepartment of Neurosurgery, Hokuto Social Medical Corporation, Hokuto HospitalGoodman Cancer Institute, McGill UniversityResearch Institute of the McGill University Health CentreAbstract High grade gliomas (HGG) are incurable brain cancers, where inevitable disease recurrence is driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) chemotherapy, amidst weak immune and natural killer (NK) cell surveillance. The present study was designed to understand how to enhance the contribution of innate immunity to post TMZ disease control. Strikingly, molecular subtypes of HGG impacted the repertoire of NK cell sensitivity markers across human HGG transcriptomes, and in a panel of GSCs with either proneural (PN-GSC) or mesenchymal (MES-GSC) phenotypes. Indeed, only MES-GSCs (but not PN-GSCs) were enriched for NK cell ligands and sensitive to NK-mediated cytotoxicity in vitro. While NK cells alone had no effect on HGG progression in vivo, the post-chemotherapy (TMZ) recurrence of MES-GSC-driven xenografts was aborted by timed intracranial injection of live or irradiated NK (NK92MI) cells, resulting in long term survival of animals. This curative effect declined when NK cell administration was delayed relative to TMZ exposure pointing to limits of the immune control over resurging residual tumour stem cell populations that survived chemotherapy. Overall, these results suggest that chemotherapy-dependent tumour depopulation may create a unique window of opportunity for NK-mediated intervention with curative effects restricted to a subset of HGGs driven by mesenchymal brain tumour initiating cells.https://doi.org/10.1186/s40478-025-01984-3High grade gliomaGlioblastomaMesenchymal glioma stem cellsProneural glioma stem cellsNK cellsTemozolomide |
| spellingShingle | Brian Meehan Lata Adnani Xianbing Zhu Nadim Tawil Delphine Garnier Ichiro Nakano Sidong Huang Janusz Rak Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells Acta Neuropathologica Communications High grade glioma Glioblastoma Mesenchymal glioma stem cells Proneural glioma stem cells NK cells Temozolomide |
| title | Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells |
| title_full | Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells |
| title_fullStr | Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells |
| title_full_unstemmed | Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells |
| title_short | Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells |
| title_sort | curative timed nk cell based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells |
| topic | High grade glioma Glioblastoma Mesenchymal glioma stem cells Proneural glioma stem cells NK cells Temozolomide |
| url | https://doi.org/10.1186/s40478-025-01984-3 |
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