Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment.
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Brain Neoplasms
/ drug therapy
Cytokines
/ metabolism
Female
Glioblastoma
/ drug therapy
Humans
Immunotherapy
Mice
Mice, Inbred C57BL
Myeloid Cells
/ drug effects
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Receptors, CXCR4
/ antagonists & inhibitors
Survival Rate
Tumor Microenvironment
/ drug effects
Xenograft Model Antitumor Assays
CXCR4
Checkpoint inhibitor
Glioma
Immunotherapy
PD-1
Journal
Journal of neuro-oncology
ISSN: 1573-7373
Titre abrégé: J Neurooncol
Pays: United States
ID NLM: 8309335
Informations de publication
Date de publication:
Jun 2019
Jun 2019
Historique:
received:
18
02
2019
accepted:
13
04
2019
pubmed:
27
4
2019
medline:
18
12
2019
entrez:
27
4
2019
Statut:
ppublish
Résumé
Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.
Sections du résumé
BACKGROUND
BACKGROUND
Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model.
METHODS
METHODS
C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry.
RESULTS
RESULTS
Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines.
CONCLUSIONS
CONCLUSIONS
Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.
Identifiants
pubmed: 31025274
doi: 10.1007/s11060-019-03172-5
pii: 10.1007/s11060-019-03172-5
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
CXCR4 protein, mouse
0
Cytokines
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Receptors, CXCR4
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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