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Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma
BACKGROUND: Despite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide (TMZ) as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252128/ https://www.ncbi.nlm.nih.gov/pubmed/35795471 http://dx.doi.org/10.1093/noajnl/vdac076 |
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author | Daniel, Paul Meehan, Brian Sabri, Siham Jamali, Fatemeh Sarkaria, Jann N Choi, Dongsic Garnier, Delphine Kitange, Gaspar Glennon, Kate I Paccard, Antoine Karamchandani, Jason Riazalhosseini, Yasser Rak, Janusz Abdulkarim, Bassam |
author_facet | Daniel, Paul Meehan, Brian Sabri, Siham Jamali, Fatemeh Sarkaria, Jann N Choi, Dongsic Garnier, Delphine Kitange, Gaspar Glennon, Kate I Paccard, Antoine Karamchandani, Jason Riazalhosseini, Yasser Rak, Janusz Abdulkarim, Bassam |
author_sort | Daniel, Paul |
collection | PubMed |
description | BACKGROUND: Despite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide (TMZ) as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has yet to be described. METHODS: We combined GBM patient and derive GBM stem cells (GSCs) from tumors following TMZ to explore response of hypermutant and non-hypermutant emergent phenotypes and explore the immune relevance of hypermutant and non-hypermutant states in vivo. RESULTS: Hypermutation emerges as one of two possible mutational subtypes following TMZ treatment in vivo and demonstrates distinct phenotypic features compared to non-hypermutant recurrent GBM. Hypermutant tumors elicited robust immune rejection in subcutaneous contexts which was accompanied by increased immune cell infiltration. In contrast, immune rejection of hypermutant tumors were stunted in orthotopic settings where we observe limited immune infiltration. Use of anti-PD-1 immunotherapy showed that immunosuppression in orthotopic contexts was independent from the PD-1/PD-L1 axis. Finally, we demonstrate that mutational burden can be estimated from DNA contained in extracellular vesicles (EVs). CONCLUSION: Hypermutation post-TMZ are phenotypically distinct from non-hypermutant GBM and requires personalization for appropriate treatment. The brain microenvironment may be immunosuppressive and exploration of the mechanisms behind this may be key to improving immunotherapy response in this subtype of recurrent GBM. |
format | Online Article Text |
id | pubmed-9252128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-92521282022-07-05 Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma Daniel, Paul Meehan, Brian Sabri, Siham Jamali, Fatemeh Sarkaria, Jann N Choi, Dongsic Garnier, Delphine Kitange, Gaspar Glennon, Kate I Paccard, Antoine Karamchandani, Jason Riazalhosseini, Yasser Rak, Janusz Abdulkarim, Bassam Neurooncol Adv Basic and Translational Investigations BACKGROUND: Despite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide (TMZ) as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has yet to be described. METHODS: We combined GBM patient and derive GBM stem cells (GSCs) from tumors following TMZ to explore response of hypermutant and non-hypermutant emergent phenotypes and explore the immune relevance of hypermutant and non-hypermutant states in vivo. RESULTS: Hypermutation emerges as one of two possible mutational subtypes following TMZ treatment in vivo and demonstrates distinct phenotypic features compared to non-hypermutant recurrent GBM. Hypermutant tumors elicited robust immune rejection in subcutaneous contexts which was accompanied by increased immune cell infiltration. In contrast, immune rejection of hypermutant tumors were stunted in orthotopic settings where we observe limited immune infiltration. Use of anti-PD-1 immunotherapy showed that immunosuppression in orthotopic contexts was independent from the PD-1/PD-L1 axis. Finally, we demonstrate that mutational burden can be estimated from DNA contained in extracellular vesicles (EVs). CONCLUSION: Hypermutation post-TMZ are phenotypically distinct from non-hypermutant GBM and requires personalization for appropriate treatment. The brain microenvironment may be immunosuppressive and exploration of the mechanisms behind this may be key to improving immunotherapy response in this subtype of recurrent GBM. Oxford University Press 2022-05-23 /pmc/articles/PMC9252128/ /pubmed/35795471 http://dx.doi.org/10.1093/noajnl/vdac076 Text en © The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Basic and Translational Investigations Daniel, Paul Meehan, Brian Sabri, Siham Jamali, Fatemeh Sarkaria, Jann N Choi, Dongsic Garnier, Delphine Kitange, Gaspar Glennon, Kate I Paccard, Antoine Karamchandani, Jason Riazalhosseini, Yasser Rak, Janusz Abdulkarim, Bassam Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma |
title | Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma |
title_full | Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma |
title_fullStr | Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma |
title_full_unstemmed | Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma |
title_short | Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma |
title_sort | detection of temozolomide-induced hypermutation and response to pd-1 checkpoint inhibitor in recurrent glioblastoma |
topic | Basic and Translational Investigations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252128/ https://www.ncbi.nlm.nih.gov/pubmed/35795471 http://dx.doi.org/10.1093/noajnl/vdac076 |
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