Exportin 1 (XPO1) blockade regulates immunosuppressive function of tumor myeloid derived suppressor cells

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Presentation Time: 01:45 PM - 02:00 PM
Abstract ID: 4294 - B

Presenting Author:
Saeed Daneshmandi , Post Doc at Roswell Park Comp. Cancer Ctr.

Abstract:

Myeloid-derived suppressor cells (MDSCs) are key regulators of immune responses in the tumor microenvironment (TME). Here we report the pivotal role played by Exportin 1 (XPO1) in shaping the phenotype and suppressive function of tumor associated MDSCs, thereby influencing tumor progression. Using the EL-4 murine tumor model, we demonstrated that tumor MDSCs exhibit elevated levels of XPO1, that drive their immunosuppressive activity. We showed that the XPO1 inhibition can effectively remodel MDSCs phenotype and functions, resulting in enhanced anti-tumor responses and the suppression of tumor growth. We showed that depletion of MDSC by anti-Ly6C antibody, restore tumor growth post XPO1 blockade. Unbiased proteomic analysis revealed that nuclear export of ERK1/2 by XPO1 is pivotal for IL-6 mediated MAPK signaling, which underpins MDSC immunosuppressive functions. Importantly, our data confirm that blockade of XPO1 function by Selinexor (an XPO1 inhibitor), sequesters ERK1/2 in the MDSC nucleus. This results in the suppression of IL-6 mediated MAPK signaling, a shift in transcriptional profiles toward the induction of neutrophil-like immunostimulatory cells. Our study demonstrates that XPO1 inhibition transforms tumor MDSCs into immune-stimulating neutrophil-like cells, reducing tumor growth and prolonging survival in pre-clinical tumor models. These results reveal novel targets for MDSC reprogramming to enhance cancer treatment outcomes in clinical practice.