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

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. Overall design: MDSCs were generated in vitro using IL-6 (40 ng/ml) and GM-CSF (40 ng/ml) for 4 days in presence of Selinexor (50 nM) of vehicle (DMSO) and their transcriptomics profile was evaluated by single cell RNA sequencing (scRNA-seq).