Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

/pdf/myeloid-derived-suppressor-cells-as-regulators-of-the-immune-4w2mvge6zg.pdf

Myeloid-derived suppressor cells as regulators of the immune system.

Many cancer immunotherapies developed in experimental animals have been tested in clinical trials. Although some have shown modest clinical effects, most have not been effective. Recent studies have identified myeloid-origin cells that are potent suppressors of tumor immunity and therefore a significant impediment to cancer immunotherapy. "Myeloid-derived suppressor cells" (MDSC) accumulate in the blood, lymph nodes, and bone marrow and at tumor sites in most patients and experimental animals with cancer and inhibit both adaptive and innate immunity. MDSC are induced by tumor-secreted and host-secreted factors, many of which are proinflammatory molecules. The induction of MDSC by proinflammatory mediators led to the hypothesis that inflammation promotes the accumulation of MDSC that down-regulate immune surveillance and antitumor immunity, thereby facilitating tumor growth. This article reviews the characterization and suppressive mechanisms used by MDSC to block tumor immunity and describes the mechanisms by which inflammation promotes tumor progression through the induction of MDSC.

Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathologic conditions ranging from cancer to obesity. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. MDSCs are characterized by a distinct set of genomic and biochemical features, and can, on the basis of recent findings, be distinguished by specific surface molecules. The salient feature of these cells is their ability to inhibit T cell function and thus contribute to the pathogenesis of various diseases. In this Review, we discuss the origin and nature of these cells; their distinctive features; and their biological roles in cancer, infectious diseases, autoimmunity, obesity and pregnancy.

Myeloid-derived suppressor cells coming of age.

Para-inflammation in the aging retina.

Myeloid-derived suppressor cells (MDSC) accumulate in most cancer patients and experimental animals with cancer. They accumulate in response to pro-inflammatory mediators and they use a variety of mechanisms to block both innate and adaptive antitumor immunity. Because of their critical role in obstructing immune responses, MDSC are a strategic obstacle to immunotherapies that require activation of the host’s cell-mediated and innate immune responses. Following a brief description of the factors that induce MDSC accumulation, this article reviews two newly discovered mechanisms that MDSC use to suppress the activation of CD4+ and CD8+ T cells. The first mechanism is MDSC sequestration of cysteine, an amino acid that T cells are unable to synthesize de novo and that they require for activation. The second mechanism is MDSC-mediated down-regulation of l-selectin. T cells must have an l-selectinhigh phenotype to home to lymph nodes and inflammatory sites where they encounter antigen and are activated. By down-regulating l-selectin on T cells, MDSC perturb T cell trafficking patterns and thereby inhibit T cell activation. Given the complexity of conditions that regulate MDSC accumulation and the variety of suppressive mechanisms used by MDSC, it is essential to understand which conditions and mechanisms are dominant so MDSC accumulation and/or activity can be targeted in individual patients to minimize MDSC-induced immune suppression.

/pdf/myeloid-derived-suppressor-cells-more-mechanisms-for-myzr2umhlc.pdf

Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity.

Analysis of Retinal Cellular Infiltrate in Experimental Autoimmune Uveoretinitis Reveals Multiple Regulatory Cell Populations

Macrophage responses are regulated by multiple secreted factors as well as by cell surface receptors, including the inhibitory signals resulting from ligation of myeloid CD200 receptors (CD200R) by the widely distributed CD200. In the absence of CD200, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. In these current experiments, an agonist monoclonal rat anti-mouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)γ-mediated nitric oxide (NO) and interleukin-6 production. Experimental autoimmune uveoretinitis (EAU) was used as a model of organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression. In mice lacking CD200 (CD200−/−), increased numbers of retina-infiltrating macrophages displaying heightened NO responses were observed during EAU. In addition, we aimed to suppress disease by maintaining tonic suppression of macrophage activation via CD200R. Systemically administered DX109 monoclonal antibody suppressed EAU despite maintained T-cell proliferation and IFNγ production. Furthermore, locally administered DX109 monoclonal antibody resulted in an earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signaling can successfully prevent full expression of IFNγ-mediated macrophage activation and protect against tissue damage during autoimmune responses.

/pdf/monoclonal-antibody-mediated-cd200-receptor-signaling-2su8f0wfb4.pdf

Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis.

Purpose EAU is an established preclinical model for assessment of immunotherapeutic efficacy toward translation of therapy for posterior uveitis. Reliable screening of clinical features that correlate with underlying retinal changes and damage has not been possible to date. This study was undertaken to describe, validate, and correlate topical endoscopic fundus imaging (TEFI) with histologic features of murine experimental autoimmune uveoretinitis (EAU), with the intent of generating a rapid noninvasive panretinal assessment of ocular inflammation. Methods EAU was induced in B10.RIII mice by immunization with the peptide RBP-3(161-180). The clinical disease course (days 0-63) was monitored and documented using TEFI. Disease severity and pathology were confirmed at various time points by histologic assessment. The composition of the cell infiltrate was also examined and enumerated by flow cytometry. Results TEFI demonstrated the hallmark features of EAU, paralleling many of the clinical features of human uveitis, and closely aligned with underlying histologic changes, the severity of which correlated significantly with the number of infiltrating retinal leukocytes. Leukocytic infiltration occurred before manifestation of clinical disease and clinically fulminant disease, as well as cell infiltrate, resolved faster than histologic scores. During the resolution phase, neither the clinical appearance nor number of infiltrating retinal leukocytes returned to predisease levels. Conclusions In EAU, there is a strong correlation between histologic severity and the number of infiltrating leukocytes into the retina. TEFI enhances the monitoring of clinical disease in a rapid and noninvasive fashion. Full assessment of preclinical immunotherapeutic efficacy requires the use of all three parameters: TEFI, histologic assessment, and flow cytometric analysis of retinal infiltrate.

The clinical time-course of experimental autoimmune uveoretinitis using topical endoscopic fundal imaging with histologic and cellular infiltrate correlation.

In chronic inflammation, across a number of quite different pathological conditions, monocytes accumulate. In autoimmune disease, these cells are widely recognised to play an inflammatory and tissue destructive role. But these cells also inhibit T cell proliferation by a range of different mechanisms that are accompanied by the depletion of specific amino acids in the local microenvironment and the downregulation of the T cell receptor ζ chain. This occurs within the pro-inflammatory environment and in the presence of Th1 (IFNγ) and Th17 (IL-17) cytokines. In tumours, related cells are part of a population called myeloid-derived suppressor cells (MDSC) and they are associated with immunosuppression. Their depletion can lead to clinical improvement. In organ specific autoimmune disease, where such cells can be found in the spleen and in target organs, recent evidence indicates that they may play a role in limiting the T cell response to autoantigens in the target tissue. This occurs by a targeted disruption of T cell division. In this review we discuss evidence for the presence on MDSC in murine and human autoimmune disease and the mechanisms by which such cells inhibit T cell proliferation.

Monocyte dependent regulation of autoimmune inflammation.

Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b + macrophages and CD4 + T cells into the normally immune-privileged retina Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages The majority of immune cells infiltrating into the retina are CD11b + myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-γ and IL-17 T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-γ and autocrine TNF-α signaling in the myeloid cells via TNFR1 In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction

/pdf/tnfr1-dependent-regulation-of-myeloid-cell-function-in-2pqljhv6ox.pdf

Ben J. E. Raveney

Papers

Analysis of Retinal Cellular Infiltrate in Experimental Autoimmune Uveoretinitis Reveals Multiple Regulatory Cell Populations

Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis.

The clinical time-course of experimental autoimmune uveoretinitis using topical endoscopic fundal imaging with histologic and cellular infiltrate correlation.

Monocyte dependent regulation of autoimmune inflammation.

TNFR1-dependent regulation of myeloid cell function in experimental autoimmune uveoretinitis.