Tumor-Induced Tolerance and Immune Suppression Depend on the C/EBPβ Transcription Factor

Abstract

Tumor growth is associated with a profound alteration in myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). We showed that among factors produced by various experimental tumors, the cytokines GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of CD8(+) T cells and allow long term acceptance of pancreatic islet allografts. Cytokines inducing MDSCs acted on a common molecular pathway and the immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on the C/EBPbeta transcription factor. Adoptive transfer of tumor antigen-specific CD8(+) T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBPbeta in the myeloid compartment, suggesting that C/EBPbeta is a critical regulator of the immunosuppressive environment created by growing cancers.

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

“…Bone marrow cells were cultured in the presence of GM-CSF and IL-6 as previously described. 15 After 4 d, most cells showed double expression of Gr1 and CD11b and strongly suppressed T-cell proliferation. These bone marrow-derived MDSC (BM-MDSC) were stimulated in culture with R848 for 48 h. As seen previously with MDSC following TLR7 treatment in vivo, we observed an increase in differentiation markers (F4/80 and CD11c) and maturation markers (MHC-I and MHC-II) on BM-MDSC upon in vitro R848 stimulation (Fig.…”

“…15 After red blood cell lysis (BD Pharm Lyse, BD Biosciences), cells were cultured in complete medium supplemented with 40 ng/mL GM-CSF and 40 ng/mL IL-6 (both from PeproTech, Rocky Hill, NJ) and harvested at day 4. The percentage of Gr1 C CD11b C cells was over 90%.…”

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

“…More recently, C/EBPb was proposed as another transcription factor for the activation and functional suppression of MDSCs. 23 Although the role of STAT3 in C/ EBPb expression is not known, the requirement of IL-6 for the in vitro generation of immunosuppressive MDSCs suggests that STAT3 activation might be required for C/EBPb-dependent immunosuppression by MDSCs.…”

“…22 Additionally, C/EBPb has been suggested to be a master regulator for the immunosuppressive function of MDSCs. 23 We hypothesized that while TLR ligation on effector cells is indispensible for the successful eradication of the tumor, Myd88 signaling in MDSCs might mediate suppressive function. In this study, we investigated the role of Myd88 in the immunosuppressive function of MDSCs against CD4 þ and CD8 þ T cells and assessed methods to block the Myd88-mediated suppressive function of MDSCs without inhibiting effector cells.…”

Phenotypic and functional dissection of myeloid-derived suppressor cells

“…In turn, the increase in S100A8 and S100A9 inhibits dendritic cell differentiation and promotes the MDSC expansion, accumulation, and the recruitment the MDSCs to the tumor site (Cheng et al 2008). CCAATenhancer-binding protein b which is reported as a crucial factor for the MDSC expansion is also upregulated by STAT3 (Marigo et al 2010). In addition, STAT3 increases the transcription of p47 phox which is a component of nicotinamide adenine dinucleotide phosphate oxidase (NOX2).…”