Genetic driver mutations introduced in identical cell‐of‐origin in murine glioblastoma reveal distinct immune landscapes but similar response to checkpoint blockade

Glioblastoma (GBM) is the most aggressive primary brain tumor. In addition to being genetically heterogeneous, GBMs are also immunologically heterogeneous. However, whether the differences in immune microenvironment are driven by genetic driver mutation is unexplored. By leveraging the versatile RCA...

Full description

Saved in:
Bibliographic Details
Published in:Glia 2020-10, Vol.68 (10), p.2148-2166
Main Authors: Chen, Zhihong, Herting, Cameron J., Ross, James L., Gabanic, Ben, Puigdelloses Vallcorba, Montse, Szulzewsky, Frank, Wojciechowicz, Megan L., Cimino, Patrick J., Ezhilarasan, Ravesanker, Sulman, Erik P., Ying, Mingyao, Ma'ayan, Avi, Read, Renee D., Hambardzumyan, Dolores
Format: Article
Language:English
Subjects:
Animal models
Brain cancer
Brain tumors
Cells (biology)
EGFRvIII
GEMM of GBM
Gene transfer
Glioblastoma
Immune checkpoint
Immune system
Irradiation
microenvironment
Microenvironments
Mimicry
Mutation
Myeloid cells
Nestin
Neural stem cells
PD-L1 protein
PD‐L1
Progenitor cells
Radiation
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Glioblastoma (GBM) is the most aggressive primary brain tumor. In addition to being genetically heterogeneous, GBMs are also immunologically heterogeneous. However, whether the differences in immune microenvironment are driven by genetic driver mutation is unexplored. By leveraging the versatile RCAS/tv‐a somatic gene transfer system, we establish a mouse model for Classical GBM by introducing EGFRvIII expression in Nestin‐positive neural stem/progenitor cells in adult mice. Along with our previously published Nf1‐silenced and PDGFB‐overexpressing models, we investigate the immune microenvironments of the three models of human GBM subtypes by unbiased multiplex profiling. We demonstrate that both the quantity and composition of the microenvironmental myeloid cells are dictated by the genetic driver mutations, closely mimicking what was observed in human GBM subtypes. These myeloid cells express high levels of the immune checkpoint protein PD‐L1; however, PD‐L1 targeted therapies alone or in combination with irradiation are unable to increase the survival time of tumor‐bearing mice regardless of the driver mutations, reflecting the outcomes of recent human trials. Together, these results highlight the critical utility of immunocompetent mouse models for preclinical studies of GBM, making these models indispensable tools for understanding the resistance mechanisms of immune checkpoint blockade in GBM and immune cell‐targeting drug discovery. Genetic driver mutations dictate the immune composition of GBM subtypes. Immunosuppressive myeloid cells express high‐level PD‐L1. Immunocompetent mouse models are essential tools to understand the resistance mechanisms of anti‐PD‐L1 therapy in GBM.
ISSN:0894-1491
1098-1136
DOI:10.1002/glia.23883