| Title: |
Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma. |
| Authors: |
Yeo, Alan T; Shah, Rushil; Aliazis, Konstantinos; Pal, Rinku; Xu, Tuoye; Zhang, Piyan; Rawal, Shruti; Rose, Christopher M; Varn, Frederick S; Appleman, Vicky A; Yoon, Joon; Varma, Hemant; Gygi, Steven P; Verhaak, Roel G W; Boussiotis, Vassiliki A; Charest, Al |
| Source: |
Faculty Research 2023 |
| Publisher Information: |
The Mouseion at the JAXlibrary |
| Publication Year: |
2023 |
| Collection: |
The Jackson Laboratory: The Mouseion at the JAXlibrary |
| Subject Terms: |
JGM; Animals; Mice; Glioblastoma; CTLA-4 Antigen; Programmed Cell Death 1 Receptor; Cell Line; Tumor; Immunotherapy; Myeloid-Derived Suppressor Cells; Mutation; Tumor Microenvironment; Brain Neoplasms |
| Description: |
The composition of the tumor immune microenvironment (TIME) is considered a key determinant of patients' response to immunotherapy. The mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) is a lethal primary brain cancer for which there are no curative treatments. GBMs are immunologically heterogeneous and impervious to checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models of GBM, we identified distinct immune landscapes associated with expression of EGFR wild-type and mutant EGFRvIII cancer driver mutations. Over time, accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) was more pronounced in EGFRvIII-driven GBMs and was correlated with resistance to PD-1 and CTLA-4 combination checkpoint blockade immunotherapy. We determined that GBM-secreted CXCL1/2/3 and PMN-MDSC-expressed CXCR2 formed an axis regulating output of PMN-MDSCs from the bone marrow leading to systemic increase in these cells in the spleen and GBM tumor-draining lymph nodes. Pharmacologic targeting of this axis induced a systemic decrease in the numbers of PMN-MDSC, facilitated responses to PD-1 and CTLA-4 combination checkpoint blocking immunotherapy, and prolonged survival in mice bearing EGFRvIII-driven GBM. Our results uncover a relationship between cancer driver mutations, TIME composition, and sensitivity to checkpoint blockade in GBM and support the stratification of patients with GBM for checkpoint blockade therapy based on integrated genotypic and immunologic profiles. |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://mouseion.jax.org/stfb2023/158; https://mouseion.jax.org/context/stfb2023/article/1139/viewcontent/36881002.pdf |
| DOI: |
10.1158/2326-6066.Cir-22-0655 |
| Availability: |
https://mouseion.jax.org/stfb2023/158; https://doi.org/10.1158/2326-6066.Cir-22-0655; https://mouseion.jax.org/context/stfb2023/article/1139/viewcontent/36881002.pdf |
| Accession Number: |
edsbas.F9D90F8B |
| Database: |
BASE |