IFN‐γ regulates survival and function of tumor‐induced CD11b+Gr‐1high myeloid derived suppressor cells by modulating the anti‐apoptotic molecule Bcl2a1 |
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| Authors: | José Medina‐Echeverz Lydia A Haile Fei Zhao Jaba Gamrekelashvili Chi Ma Jean‐Yves Métais Cynthia E Dunbar Veena Kapoor Michael P Manns Firouzeh Korangy Tim F Greten |
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| Institution: | 1. GI‐Malignancy Section, Thoracic and GI‐Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;2. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA;3. Experimental Transplantation and Immunology Branch, National Institutes of Health, Bethesda, USA;4. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany |
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| Abstract: | Myeloid derived suppressor cells (MDSCs) play a critical role in suppression of immune responses in cancer and inflammation. Here, we describe how regulation of Bcl2a1 by cytokines controls the suppressor function of CD11b+Gr‐1high granulocytic MDSCs. Coculture of CD11b+Gr‐1high granulocytic MDSCs with antigen‐stimulated T cells and simultaneous blockade of IFN‐γ by the use of anti‐IFN‐γ blocking antibody, IFN‐γ?/? effector T cells, IFN‐γR?/? MDSCs or STAT1?/? MDSCs led to upregulation of Bcl2a1 in CD11b+Gr‐1high cells, improved survival, and enhanced their suppressor function. Molecular studies revealed that GM‐CSF released by antigen‐stimulated CD8+ T cells induced Bcl2a1 upregulation, which was repressed in the presence of IFN‐γ by a direct interaction of phosphorylated STAT‐1 with the Bcl2a1 promotor. Bcl2a1 overexpressing granulocytic MDSCs demonstrated prolonged survival and enhanced suppressor function in vitro. Our data suggest that IFN‐γ/ STAT1‐dependent regulation of Bcl2a1 regulates survival and thereby suppressor function of granulocytic MDSCs. |
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| Keywords: | Bcl2a1 G‐MDSC GM‐CSF IFN‐γ Immunotherapy Vaccine |
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