Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.

Autor: Daneshmandi S; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Yan Q; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Choi JE; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Katsuta E; Department of Oncology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan., MacDonald CR; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Goruganthu M; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Roberts N; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Repasky EA; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Singh PK; Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Attwood K; Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Wang J; Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Landesman Y; Karyopharm Therapeutics, Newton, MA, USA., McCarthy PL; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Mohammadpour H; Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. hemn.mohammadpour@roswellpark.org.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2024 Aug; Vol. 21 (8), pp. 873-891. Date of Electronic Publication: 2024 Jun 20.
DOI: 10.1038/s41423-024-01187-1
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to CSI and USTC.)
Databáze: MEDLINE
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