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Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

ABSTRACT: Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

PROVIDER: PRJNA624324 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11523543_1.fastq.gz	Fastqsanger.gz
	SRR11523543_2.fastq.gz	Fastqsanger.gz
	SRR11523544_1.fastq.gz	Fastqsanger.gz
	SRR11523544_2.fastq.gz	Fastqsanger.gz
	SRR11523545_1.fastq.gz	Fastqsanger.gz

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Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner.

Project description: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.See related commentary by Gabrilovich et al., p. 1100.This article is highlighted in the In This Issue feature, p. 1079.

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Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

Project description:We report that monocytic (mMDSC) and granulocytic (gMDSC) MDSC susbsets have distinct expression profiles with ~300-1200 genes uniquely expressed on each subset. We further used these genes for pathway annotation. Our findings identified that mMDSC and gMDSC have unique pathway associations that can be targeted via distinct drug candidates.

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Project description:Increased myeloid-derived suppressor cell (MDSC) frequency is associated with worse outcomes and poor therapeutic response in multiple types of cancer. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared to granulocytic (g) MDSCs has yet to be determined. Here we performed first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in their behavior and found that mMDSCs and gMDSCs display differences in their tumor-accelerating ability, with mMDSCs driving tumor growth in GBM models. Epigenetic assessments revealed enhanced gene accessibility for cell adhesion programs in mMDSCs and higher integrin b1 expression and function in mouse and human mMDSCs. Integrin b1 blockage abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment. These findings suggest that integrin b1 expression underlies the enrichment of mMDSCs in tumors and represents a putative immunotherapy target to attenuate myeloid cell-driven immune suppression in GBM.

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