Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma.

Autor:	Daniel P; Department of Oncology, McGill University, Research Institute of the McGill University Health Centre (Research Institute-MUHC), Montreal, Canada., Meehan B; McGill University, Research Institute of the McGill University Health Centre (Research Institute-MUHC), Montreal, Canada., Sabri S; Research Institute, Cancer Research Program, McGill University Health Centre, Glen Site, 1001 Decarie Boulevard, Montreal, Quebec H4A 3J1, Canada., Jamali F; McGill University, Research Institute of the McGill University Health Centre (Research Institute-MUHC), Montreal, Canada., Sarkaria JN; Mayo Clinic, Department of Radiation Oncology., Choi D; McGill University, Research Institute of the McGill University Health Centre (Research Institute-MUHC), Montreal, Canada., Garnier D; McGill University, Research Institute of the McGill University Health Centre (Research Institute-MUHC), Montreal, Canada., Kitange G; Mayo Clinic, Department of Radiation Oncology., Glennon KI; McGill University, McGill Genome Centre., Paccard A; McGill University, McGill Genome Centre., Karamchandani J; Department of Pathology, McGill University, Montreal, Canada., Riazalhosseini Y; McGill University, McGill Genome Centre., Rak J; Department of Pediatrics, McGill University Health Centre, Glen Site, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada., Abdulkarim B; Department of Oncology, McGill University, Research Institute of the McGill University Health Centre (Research Institute-MUHC), Montreal, Canada.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2022 May 23; Vol. 4 (1), pp. vdac076. Date of Electronic Publication: 2022 May 23 (Print Publication: 2022).
DOI:	10.1093/noajnl/vdac076
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
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