Document Type
Article
Publication Date
5-3-2023
Original Citation
Yeo A,
Shah R,
Aliazis K,
Pal R,
Xu T,
Zhang P,
Rawal S,
Rose C,
Varn F,
Appleman V,
Yoon J,
Varma H,
Gygi S,
Verhaak R,
Boussiotis V,
Charest A.
Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma. Cancer Immunol Res. 2023;11(5):629-45
Keywords
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
JAX Source
Cancer Immunol Res. 2023;11(5):629-45
ISSN
2326-6074
PMID
36881002
DOI
https://doi.org/10.1158/2326-6066.Cir-22-0655
Grant
NIH grants R01 CA 185137 (to S.P. Gygi, A. Charest), R01 CA229784 (to V.A. Boussiotis, A. Charest), and R01 CA238263 (to V.A. Boussiotis).
Abstract
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.
Comments
This open access article is distributed under the Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.