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Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells (iMDSCs) ameliorate xenogeneic GVHD

ABSTRACT: Acute graft versus host disease (aGVHD) is considered a major complication of allogeneic hematopoietic stem cell transplant (aHSCT). Front-line pharmaceutical treatment is not uniformly effective and has toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent immunosuppressive functions. Their potential to control GVHD has been proven in different rodent models. However, a high MDSC to T cell ratio and multiple doses of MDSCs are needed to achieve maximum effectiveness. Clinical translation of in vitro MDSC generation limits its clinical usage by a relatively low yield and need for personalized patient products, especially challenging for multiple treatment courses. Therefore, we developed an in vitro method to generate MDSCs on a large scale from a human induced pluripotent stem cell (iPSC)-derived CD34+ cells. iMDSCs shared a similar morphology, phenotype, and suppressive function with peripheral blood (PB)-MDSCs. In striking contrast to PB-MDSCs, iMDSCs retained 95% of suppressor function when exposed to the damage-associated molecular pattern stimuli, LPS + ATP, released during GVHD. RNAseq analysis and gene knockdown studies revealed that inflammasome-resistant iMDSCs maintained expression of phosphoglycerate dehydrogenase, an enzyme involved in purine metabolism. Consistent with the retention of suppressor function during lethal xenogeneic GVHD-induced tissue injury, recipients of human iMDSCs and peripheral blood mononuclear cells (PBMC) experienced therapeutic benefits. Together, these data provide a platform for translating in vitro generated, off-the-shelf iMDSCs into the clinic for suppressing GVHD and other adverse immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246047 | GEO | 2025/09/30

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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Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells (iMDSCs) ameliorate xenogeneic GVHD

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