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Expression data from MDSCs at different time points during tumor progression

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were down-regulated, but pro-tumor function-related genes were up-regulated in both Mo-MDSCs and PMN-MDSCs at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo- and PMN-MDSCs isolated from the late time points. Experiments using siRNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing iNOS, ARG1, and ROS levels and enhancing NF-kappaB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE35398 | GEO | 2012/03/30

SECONDARY ACCESSION(S): PRJNA152783

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

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Expression data from MDSCs at different time points during tumor progression

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