Novel murine glioblastoma models that reflect the immunotherapy resistance profile of a human disease

Chao Hsien Chen, Renee L. Chin, Genevieve P. Hartley, Spencer T. Lea, Brian J. Engel, Cheng En Hsieh, Rishika Prasad, Jason Roszik, Takashi Shingu, Gregory A. Lizee, Amy B. Heimberger, Steven W. Millward, Jian Hu, David S. Hong, Michael A. Curran*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations

Abstract

Background. The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2 QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms. Methods. The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice.The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. Results. QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improvedT cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. Conclusions. These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.

Original languageEnglish
Pages (from-to)1415-1427
Number of pages13
JournalNeuro-Oncology
Volume25
Issue number8
DOIs
StatePublished - 01 08 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Keywords

  • Anti-CTLA-4
  • anti-PD-1
  • glioblastoma
  • immunotherapy

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