Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Abstract

IntroductionImmune-based therapy has achieved a certain level of success; however, the overall therapeutic effect has been much less promising due to the immune suppressive mechanisms associated with advanced malignancies. 1 To achieve a better therapeutic efficacy of immune activation therapy, the mechanism or mechanisms by which a large tumor burden prevents immune activation from inducing effective antitumor immunity needs to be elucidated.Tumor growth is accompanied by an increase in the number of Gr-1 ϩ Mac-1 ϩ myeloid-derived suppressor cells (MDSCs) 2-4 and tumor-specific T regulatory cells (Tregs) 5,6 with strong immune suppressive activity in cancer patients and in tumor-bearing mice. [7][8][9] Both MDSCs and Tregs may be directly involved in immune unresponsiveness in active immune therapy.It has been demonstrated that MDSCs are involved in T-cell hyporesponsiveness in tumor-bearing mice. Several mechanisms by which MDSCs regulate the tumor-specific T-cell response have recently been proposed and the in vivo immune regulatory effects of MDSCs on tumor-specific T-cell response have been identified. 7-12 T-cell inactivation can be mediated by MDSCs through IFN␥-dependent nitric oxide (NO) production [12][13][14][15][16] or the Th2-mediated IL-4/IL-13-dependent arginase 1 pathway. 14,[17][18][19][20][21][22] In addition, a mechanism of ROS-mediated cell killing has been proposed. 3,23,24 Furthermore, MDSCs can inhibit cytotoxic T lymphocyte (CTL) responses through NOdependent or -independent mechanisms. Cell-to-cell contact appeared to be crucial in these mechanisms. 25 Our laboratory has further identified a novel mechanism of MDSC-mediated immune suppression on activated T cells through the development of Foxp3 ϩ T regulatory cells (Tregs) and T-cell tolerance both in vitro and in tumor-bearing mice. The induction of Tregs by MDSCs requires IFN-␥ and IL-10 but is independent of the NO-mediated suppressive mechanism. 11 To overcome MDSCmediated immune suppression and prevent Treg induction, it is critical to identify the tumor factors that are required for MDSC accumulation in tumor-bearing animals.Several lines of evidence support the hypothesis that the development and expansion of MDSCs may be modulated by tumor-secreted factors. MDSCs in tumor-bearing animals can differentiate into mature dendritic cells or remain as MDSCs with inhibitory activities, depending on the local cytokine milieu. 26,27 Human renal cell carcinoma cell lines release soluble factors (IL-6, M-CSF) that inhibit the differentiation of CD34 ϩ cells into dendritic cells (DCs) and trigger their commitment toward monocytic cells. 28 In a transgenic mammary tumor, VEGF levels correlate with the MDSC number. 29 Moreover, the in vivo infusion of vascular endothelial growth factor (VEGF) can induce MDSC development in naive mice and impair DC function and differentiation. 30 Granulocyte macrophage-colony-stimulating factor (GM-CSF) secretion has correlated with the capacity of tumor metastases and the GM-CSF and IL-3 in conditioned mediu...

Myeloid Derived Suppressor Cells and Their Role in Diseases

“…M-CSF were found to be secreted in conjunction with IL-6 by in human renal cell carcinoma cell line, which have prevented DC generation from hematopoietic stem cells (HSCs) and triggered their commitment to monocytic cells [42]. Stem cell factor have been shown to be secreted by murine and human tumour cell lines, and tumourbearing mice, and blockade of stem cell factor function have greatly reduced MDSC expansion and enhanced tumour regression [43].…”

“…In addition to GM-CSF, several soluble factors such as granulocyte colony-stimulating factor (G-CSF) [41], macrophage colony-stimulating factor (M-CSF) [42], stem cell factor [43] and vascular endothelial growth factor (VEGF) [44] can directly induce the expansion of MDSCs.…”

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

“…In mice, the cell surface phenotype of MDSCs is identified as CD11b + and Gr-1 + . The expansion of MDSCs can be induced by the stimulatory factors of myelopoiesis such as GM-CSF, stem cell factor, and vascular endothelial growth factor (19)(20)(21), released primarily by tumor cells, and the activation of MDSCs is associated with proinflammatory mediators, including IL-1b, IL-6, PGE 2 , and S100A8/9 proteins (22)(23)(24)(25), produced by tumor cells, tumor stroma, and tumor-infiltrating immune cells. For example, IL-1b has been reported to promote tumor progression by increasing the accumulation of MDSCs (22), whereas IL-1R-deficient mice have a delayed accumulation of MDSCs and reduced tumor progression.…”

Early exposure of high-dose interleukin-4 to tumor stroma reverses myeloid cell-mediated T-cell suppression

“…Therefore, both a suitable dose and an appropriate application time are critical for exogenous IL-4 to be effective. Considering the fact that a big tumor is often accompanied by a high number of MDSCs, while small tumors are associated with low number of MDSCs in tumor-bearing host, 43 as well as the fact that IL-4R is expressed in both mouse and human MDSCs, 44,45 it will be very important to analyze whether IL-4 should be used for tumor therapy shortly after the removal of the original tumor.…”