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Effect of Nakaseomyces glabratus on BM-MDSCs

ABSTRACT: Recent studies demonstrate that the gut mycobiota plays a key role in several tumors’ development. However, the contribution of commensal fungi to prostate cancer initiation and progression remains understudied. Here, we find that Nakaseomyces glabratus (N.glabratus), is enriched in fecal, blood, and tumor samples of a subset of CRPC patients, positively correlating with patients’ poor overall survival. Oral administration of N.glabratus to castrated mice accelerated CRPC development by controlling polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, androgen deprivation therapy (ADT) increases intestinal permeability, resulting in the leakage of N.glabratus from the gut to the tumor site, where it activates PMN-MDSCs by binding to the Dectin-2 receptor. Treatment of mice with a negatively charged hydrogel blocks N.glabratus translocation to the tumor site, reducing PMN-MDSCs intratumoral infiltration and activation. Taken together, these findings reveal that the gut-to-tumor translocation of commensal fungi contributes to endocrine resistance in CRPC by enhancing the immunosuppressive microenvironment of these tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE311900 | GEO | 2025/12/02

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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Effect of Nakaseomyces glabratus on BM-MDSCs

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