Radiation with STAT3 Blockade Triggers Dendritic Cell-T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy.
Animals
Antigen Presentation
/ drug effects
Brain Neoplasms
/ immunology
Cell Communication
/ drug effects
Cell Line, Tumor
/ ultrastructure
Chemoradiotherapy
/ methods
Dendritic Cells
/ drug effects
Disease Models, Animal
Glioma
/ immunology
Humans
Immunologic Memory
/ drug effects
Mice
Pyridines
/ administration & dosage
STAT3 Transcription Factor
/ antagonists & inhibitors
T-Lymphocytes
/ drug effects
Tumor Microenvironment
/ drug effects
Tyrphostins
/ administration & dosage
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
17
12
2019
revised:
14
04
2020
accepted:
24
06
2020
pubmed:
2
7
2020
medline:
15
12
2021
entrez:
2
7
2020
Statut:
ppublish
Résumé
Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma. C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier-penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment. The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.
Identifiants
pubmed: 32605912
pii: 1078-0432.CCR-19-4092
doi: 10.1158/1078-0432.CCR-19-4092
pmc: PMC9341321
mid: NIHMS1608503
doi:
Substances chimiques
Pyridines
0
STAT3 Transcription Factor
0
Stat3 protein, mouse
0
Tyrphostins
0
WP1066
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4983-4994Subventions
Organisme : NCI NIH HHS
ID : R01 CA120813
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127001
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA093459
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS094615
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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