Abstract
Myeloid-derived suppressor cells (MDSCs) are greatly expanded in cancer patients and tumor-bearing mice. They infiltrate into tumors and modulate the tumor microenvironment. In an effort to identify molecular mediators responsible for expansion and the tumor-promoting function of MDSCs, we discovered CCAAT/enhancer binding protein alpha (C/EBPα) expression was significantly reduced in MDSCs from tumor-bearing mice compared to non-tumor-bearing hosts. Tumor-conditioned medium down-regulated C/EBPα expression, suggesting tumor secreted factors inhibiting the gene expression. Consistent with the function of C/EBPα in regulating the balance between proliferation and growth arrest in hematopoietic progenitors, myeloid lineage specific deletion of C/EBPα resulted in significantly enhanced MDSC proliferation and expansion, as well as an increase of myeloid progenitors and a decrease of mature cells. In addition, deletion of C/EBPα in MDSCs enhanced the pro-angiogenic, immune suppressive and pro-tumorigenic behavior of these cells by upregulating the production of iNOS and arginase, as well as MMP-9 and VEGF. Accordingly, tumors growing in C/EBPα conditional null mice displayed greater MDSC infiltration, increased vascularization and accelerated tumor growth. Taken together, this study reveals dual negative roles of C/EBPα in the expansion as well as pro-angiogenic and immune suppressive functions in MDSCs.
Highlights
The immune suppressive and tumor-promoting properties of Myeloid-derived suppressor cells (MDSCs) have been well established
To better understand the regulation of MDSC expansion under tumor conditions, we compared gene expression in MDSCs isolated from spleens of C57BL/6 mice with or without a derivative of Lewis Lung Carcinoma (3LL) tumors
We found the expression of C/EBPα was significantly reduced in MDSCs isolated from the spleen of tumor-bearing mice compared to non-tumor bearing mice (Fig. 1A)
Summary
The immune suppressive and tumor-promoting properties of MDSCs have been well established. MDSCs are defined by the simultaneous expression of CD11b (Mac-1), a myeloid macrophage marker, and the granulocytic marker Gr-1. They lack or have reduced expression of markers of mature myeloid cells, low levels of major histocompatibility complex (MHC) class II and co-stimulatory molecules and suppress immune responses in vitro and in vivo[1,2]. MDSCs are capable of suppressing tumor immunity through multiple direct and indirect mechanisms on T-cells, dendritic cells and natural killer cells[1,2]. They directly promote tumor growth through mechanisms of tumor angiogenesis. C/EBPα plays dual negative roles in MDSC expansion and MDSC-mediated tumor angiogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
