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

作　　者：Saeed Daneshmandi Qi Yan Jee Eun Choi Eriko Katsuta Cameron R.MacDonald Mounika Goruganthu Nathan Roberts Elizabeth A.Repasky Prashant K.Singh Kristopher Attwood Jianmin Wang Yosef Landesman Philip L.McCarthy Hemn Mohammadpour 

机构地区：[1]Department of Immunology,Roswell Park Comprehensive Cancer Center,Buffalo,NY,USA [2]Department of Cell Stress Biology,Roswell Park Comprehensive Cancer Center,Buffalo,NY,USA [3]Department of Oncology,Yokohama City University,Graduate School of Medicine,Yokohama,Japan [4]Department of Cancer Genetics&Genomics,Roswell Park Comprehensive Cancer Center,Buffalo,NY,USA [5]Department of Biostatistics&Bioinformatics,Roswell Park Comprehensive Cancer Center,Buffalo,NY,USA [6]Karyopharm Therapeutics,Newton,MA,USA [7]Department of Medicine,Roswell Park Comprehensive Cancer Center,Buffalo,NY,USA

出　　处：《Cellular & Molecular Immunology》2024年第8期873-891,共19页中国免疫学杂志（英文版）

基　　金：National Institutes of Health,National Heart Lung Blood Institute(K99 HL155792,R00HL155792 to HM);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;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.

摘　　要：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.

关 键 词：MDSCS TUMOR Exportin 1 MAPK pathway 

分 类 号：R392[医药卫生—免疫学]