Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner.
Animals
Antineoplastic Agents
/ therapeutic use
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Coculture Techniques
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Glioblastoma
/ drug therapy
Humans
Immunotherapy
Interleukin-1beta
/ antagonists & inhibitors
Male
Mice, Inbred C57BL
Mice, Transgenic
Myeloid-Derived Suppressor Cells
/ drug effects
Sex Characteristics
T-Lymphocytes
/ immunology
Vidarabine
/ analogs & derivatives
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
20
11
2019
revised:
29
02
2020
accepted:
13
04
2020
pubmed:
18
4
2020
medline:
30
11
2021
entrez:
18
4
2020
Statut:
ppublish
Résumé
Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.
Identifiants
pubmed: 32300059
pii: 2159-8290.CD-19-1355
doi: 10.1158/2159-8290.CD-19-1355
pmc: PMC7415660
mid: NIHMS1585999
doi:
Substances chimiques
Antineoplastic Agents
0
IL1B protein, mouse
0
Interleukin-1beta
0
Vidarabine
FA2DM6879K
fludarabine
P2K93U8740
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
1210-1225Subventions
Organisme : NCI NIH HHS
ID : T32 CA059366
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA243314
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221747
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007250
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102669
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109742
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2020 American Association for Cancer Research.
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