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Eur J Immunol. 2014 Aug;44(8):2457-67. doi: 10.1002/eji.201444497. Epub 2014 Jun 16.

IFN-γ regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1.

Author information

1
GI-Malignancy Section, Thoracic and GI-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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-1(high) granulocytic MDSCs. Coculture of CD11b(+) Gr-1(high) 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-1(high) 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.

KEYWORDS:

Bcl2a1; G-MDSC; GM-CSF; IFN-γ; Immunotherapy; Vaccine

PMID:
24810636
PMCID:
PMC4140991
DOI:
10.1002/eji.201444497
[Indexed for MEDLINE]
Free PMC Article

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