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Mitochondrial transfer to granulocytic myeloid-derived suppressor cells augments immunosuppressive activity

ABSTRACT: The anti-inflammatory properties of granulocytic myeloid-derived suppressor cells (G-MDSCs) promote Staphylococcus aureus (S. aureus) biofilm persistence. Evidence suggests that G-MDSC activity is not only shaped by S. aureus products but also by intrinsic metabolic programs. This study explored whether G-MDSC activity could be modulated by increasing mitochondrial abundance using a co-culture paradigm with macrophages as a mitochondrial donor. Macrophages transferred mitochondria directly to G-MDSCs via tunneling nanotubes, which enhanced G-MDSC respiration as reflected by increased basal, maximal, and spare respiratory capacity. Augmenting mitochondrial abundance in G-MDSCs enhanced T cell suppressive activity concomitant with decreased cytokine production. Adoptive transfer of macrophages in a mouse model of S. aureus prosthetic joint infection revealed mitochondrial transfer to G-MDSCs in vivo that enhanced their suppressive activity, leading to increased bacterial burden. These findings support that G-MDSCs can exploit mitochondria to augment their anti-inflammatory properties in response to S. aureus biofilm.

ORGANISM(S): Mus musculus

PROVIDER: GSE295742 | GEO | 2026/02/04

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment of most cancer patients. There MDSCs suppress both adaptive and innate immune responses, hindering immunotherapies. Moreover, many cancers are accompanied by inflammation, a processes that further intensifies MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSCs collected from tumor-bearing mice profusely release nano-scale membrane-bound extracellular vesicles, called exosomes, which carry biologically active proteins between cells and contribute directly to the immune suppressive functions of MDSC. Many studies on other cell types have shown that exosomes may also carry microRNAs (miRNAs) and messenger RNAs (mRNAs) which can also be transferred to surrounding and distant cells. However, to the best of our knowledge, the miRNA and mRNA cargo of MDSC-derived exosomes has not yet been interrogated. This study aims to identify and quantify the cargo of MDSC and their immunosuppressive exosomes to gather knowledge that can offer insights on the mechanisms by which MDSCs contribute to immune suppression, focusing on the role of exosomes as intercellular communication mediators in the tumor microenvironment. In order to achieve our objective a well-established mouse model based on a conventional mammary carcinoma (4T1 cells) and heightened inflammation (4T1 transduced to express the cytokine interleukin-1b) was used. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs and miRNAs. Relative quantitation demonstrated quantitative differences between the exosome cargo and the cargo of their parental cells, supporting the hypothesis that selective loading into the exosomes is possible. Additionally, quantitative and functional analyses of the exosome cargo generated under conventional and heightened inflammation conditions are consistent with clinical observations that inflammation is linked to cancer development.

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Mitochondrial transfer to granulocytic myeloid-derived suppressor cells augments immunosuppressive activity

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