Je-In Youn

Subsets of Myeloid-Derived Suppressor Cells in Tumor Bearing Mice

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G+Ly6Clow granulocytic and Ly6G−Ly6Chigh monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.

The biology of myeloid-derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity

Myeloid‐derived suppressor cells (MDSC) play an important role in the cellular network regulating immune responses in cancer, chronic infectious diseases, autoimmunity, and in other pathological conditions. Morphological, phenotypic and functional heterogeneity is a hallmark of MDSC. This heterogeneity demonstrates the plasticity of this immune suppressive myeloid compartment, and shows how various tumors and infectious agents can have similar biological effects on myeloid cells despite the differences in the factors that they produce to influence the immune system; however, such a heterogeneity creates ambiguity in the definition of MDSC as well as confusion regarding the origin and fate of these cells. In this review, we will discuss recent findings that help to better clarify these issues and to determine the place of MDSC within the myeloid cell lineage.

Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice.

MDSCs are a group of cells with potent immune‐suppressive activity. These cells accumulate in many pathologic conditions and play a major role in the regulation of immune responses. The nature of MDSC remains highly debatable. In cancer, most MDSCs are represented by cells with granulocytic phenotype and morphology, G‐MDSC. The relationship between G‐MDSCs and Neu remains unclear. In this study, we have found that G‐MDSCs, from tumor‐bearing, and Neu, from tumor‐free, mice share a common morphology and phenotype. However, in contrast to Neu, a substantial proportion of G‐MDSCs expressed M‐CSFR and a CD244 molecule. Neu had significantly higher phagocytic activity, expression of lysosomal proteins, and TNF‐α than corresponding G‐MDSCs, which had significantly higher activity of arginase, MPO, and ROS. In contrast to G‐MDSC, neither rested nor mobilized Neu suppressed T cells. G‐MDSC survived 2 days in culture in the presence of GM‐CSF and within 24 h, became phenotypic and functionally similar to Neu. Tumor‐associated G‐MDSC shared most characteristics of splenic G‐MDSC, rather then Neu. These data suggest that in cancer, despite morphological and phenotypic similarities, G‐MDSCs are functionally distinct from Neu and are comprised of pathologically activated precursors of Neu.

Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer

Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6ChiLy6G− inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.

Regulation of Tumor Metastasis by Myeloid-Derived Suppressor Cells

Accumulation of pathologically activated immature myeloid cells with potent immune-suppressive activity is one of the major immunological hallmarks of cancer. In recent years, it became clear that in addition to their immune-suppressive activity, myeloid-derived suppressor cells (MDSCs) influence tumor progression in a variety of ways. They are directly implicated in the promotion of tumor metastases by participating in the formation of premetastatic niches, promoting angiogenesis and tumor cell invasion. In this review, we discuss recent data describing various roles of MDSCs in the formation of tumor metastases.

Induction of myelodysplasia by myeloid-derived suppressor cells

Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.

Reciprocal Relationship between Myeloid-Derived Suppressor Cells and T Cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that play a major role in the regulation of immune responses in many pathological conditions. These cells have a common myeloid origin, relatively immature state, common genetic and biochemical profiles, and, most importantly, the ability to inhibit immune responses. Although initial studies of MDSCs were almost exclusively performed in tumor-bearing mice or cancer patients, in recent years, it became clear that MDSCs play a critical role in the regulation of different types of inflammation that are not directly associated with cancer. In this review we discuss the nature of the complex relationship between MDSCs and the different populations of CD4+ T cells.

Notch and Wingless Signaling Cooperate in Regulation of Dendritic Cell Differentiation

Dendritic cell (DC) differentiation is regulated by stroma via a network of soluble and cell-bound factors. Notch is one of the major elements of this network. Its role in DC differentiation, however, is controversial. Here, we demonstrate that activation of Notch signaling in hematopoietic progenitor cells (HPCs) promoted differentiation of conventional DCs via activation of the canonical Wingless (Wnt) pathway. Inhibition of the Wnt pathway abrogated the effect of Notch on DC differentiation. The fact that activation of the Wnt pathway in Notch-1-deficient embryonic stem cells restored DC differentiation indicates that Wnt signaling is downstream of the Notch pathway in regulating DC differentiation. Notch signaling activated the Wnt pathway in HPCs via expression of multiple members of the Frizzled family of Wnt receptors, which was directly regulated by the CSL (RPB-Jkappa) transcription factor. Thus, these data suggest a model of DC differentiation via cooperation between Wnt and Notch pathways.

Regulatory Myeloid Suppressor Cells in Health and Disease

Research in recent years has brought a wealth of information about the important role of immune suppressive myeloid cells in cancer and other diseases. There is growing evidence suggesting that the expansion of these regulatory cells may represent a common response to all forms of inflammation.

Antigen-Specific CD4+ T Cells Regulate Function of Myeloid-Derived Suppressor Cells in Cancer via Retrograde MHC Class II Signaling

Myeloid-derived suppressor cells (MDSC) play a major role in cancer-related immune suppression, yet the nature of this suppression remains controversial. In this study, we evaluated the ability of MDSCs to elicit CD4(+) T-cell tolerance in different mouse tumor models. In contrast to CD8(+) T-cell tolerance, which could be induced by MDSCs in all the tumor models tested, CD4(+) T-cell tolerance could be elicited in only one of the models (MC38) in which a substantial level of MHC class II was expressed on MDSCs compared with control myeloid cells. Mechanistic investigations revealed that MDSCs deficient in MHC class II could induce tolerance to CD8(+) T cells but not to CD4(+) T cells. Unexpectedly, antigen-specific CD4(+) T cells (but not CD8(+) T cells) could dramatically enhance the immune suppressive activity of MDSCs by converting them into powerful nonspecific suppressor cells. This striking effect was mediated by direct cell-cell contact through cross-linking of MHC class II on MDSCs. We also implicated an Ets-1 transcription factor-regulated increase in expression of Cox-2 and prostaglandin E2 in MDSCs in mediating this effect. Together, our findings suggest that activated CD4(+) T cells that are antigen specific may enhance the immune suppressive activity of MDSCs, a mechanism that might serve normally as a negative feedback loop to control immune responses that becomes dysregulated in cancer.