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Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors 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 antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.

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Data availability

The raw and processed sequencing data (single cell RNA-seq) generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE269677. All data supporting the findings of this study are available within the article or in the Supplementary Information.

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Acknowledgements

We wish to acknowledge support from Li Feng and Jeanne Prendergast from the Department of Immunology, Jesse Luce from Genomics Shared Resource, Leah Henegar from Karyopharm, Orla Maguire from the Flow Cytometry Shared Resource, and Nicholas Kisiel from the Department of Cancer Prevention & Control at Roswell Park. This study was supported by grants from the National Institutes of Health, National Heart Lung Blood Institute (K99 HL155792, R00HL155792 to HM), the Roswell Park Alliance (HM), a gift from Brendan and Elise McCarthy (PLM), and R01 CA205246 (ER). Cytometry services were provided by the Flow and Image Cytometry Shared Resource at the Roswell Park Comprehensive Cancer Center, which is supported in part by the NCI Cancer Center Support Grant NCI R50CA211108. This work was also supported by NCI grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Genomic and Flow and Image Cytometry Shared Resources. Selinexor was provided by Karyopharm, Newton, MA.

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HM and SD designed the research and interpreted the data. HM, SD, and PLM wrote the paper. SD, QY, JC, EK, CRM, YZ, MG, and NR executed the experiments and analyses; AN, ER, PS, KA, JW, and YL assisted in the analysis of the data and writing of the manuscript. All authors reviewed the manuscript and provided comments and edits.

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Correspondence to Hemn Mohammadpour.

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Advisory Board/Consulting for P.L.M.: BlueBird Biotech, Bristol-Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, Sanofi, and Takeda. Honoraria for P.L.M.: BlueBird Biotech, Bristol-Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, Sanofi, and Takeda. Employment for Y.L.: Karyopharm.

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Daneshmandi, S., Yan, Q., Choi, J.E. et al. Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01187-1

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