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

Paul Daniel, Brian Meehan, Siham Sabri, Fatemeh Jamali, Jann N. Sarkaria, Dongsic Choi, Delphine Garnier, Gaspar Kitange, Kate I. Glennon, Antoine Paccard, Jason Karamchandani, Yasser Riazalhosseini, Janusz Rak, Bassam Abdulkarim

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbervdac076
JournalNeuro-Oncology Advances
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Keywords

  • Temozolomide
  • glioblastoma
  • hypermutation
  • immune therapy
  • recurrence

PubMed: MeSH publication types

  • Journal Article

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