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Effect of mtDNA on MDSCs

ABSTRACT: Mitochondrial dysfunction is a hallmark of cellular senescence. Mitochondrial DNA (mtDNA) functions as a damage-associated molecular pattern that activates the innate immune system when released extracellularly. We examined whether senescent cells release mtDNA into the extracellular space and the consequences of this exogenous mtDNA in innate immunity. Both primary senescent cells and tumor cells undergoing therapy-induced senescence release mtDNA into the extracellular space. In vivo cross-species xenograft models using human prostate cancer cells in immunocompromised mice demonstrated the selective uptake of human mtDNA by mouse polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within the tumor microenvironment (TME). In vitro trans-well experiments confirmed the uptake of mtDNA by mouse PMN-MDSCs through extracellular vesicles (EVs). Internalized mtDNA enhanced the immunosuppressive activity of PMN-MDSCs via cGAS-STING-NF-_B activation, promoting tumor progression. Mechanistically, mtDNA released from senescent cells was mediated by voltage-dependent anion channels (VDAC), and pharmacological inhibition of VDAC reduced extracellular mtDNA levels, reversing PMN-MDSC-driven immunosuppression and improving the efficacy of chemotherapy in prostate cancer models. Thus, inhibiting mtDNA release may enable reprogramming of the immune suppressive microenvironment in patients treated with chemotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE290948 | GEO | 2025/03/24

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 mtDNA on MDSCs

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