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Exportin 1 governs the immunosuppressive functions of tumor myeloid derived suppressor cells through ERK1/2 nuclear export

ABSTRACT: Myeloid derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve anti-tumor immunity. Here, we discovered in preclinical murine models, that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and this expression is induced by IL-6 activated STAT3 during MDSC differentiation. XPO1 blockade transforms MDSCs into T cell-activating neutrophil-like cells, enhancing the anti-tumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to nuclear entrapment of ERK1/2, resulting in prevention of ERK1/2 phosphorylation post-IL-6 activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces neutrophil-like cells with immunostimulatory functions. Therefore, our findings have revealed a critical role of XPO1 in MDSC differentiation and suppressive function; exploiting these new discoveries reveals new targets to reprogram immunosuppressive MDSCs to improve cancer therapeutic responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE269677 | GEO | 2024/06/30

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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Exportin 1 governs the immunosuppressive functions of tumor myeloid derived suppressor cells through ERK1/2 nuclear export

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