Anti-inflammatory Triterpenoid Blocks Immune Suppressive Function of MDSCs and Improves Immune Response in Cancer

Nagaraj, Srinivas; Youn, Je In; Weber, Hannah; Iclozan, Cristina; Lu, Lily; Cotter, Matthew J.; Meyer, Colin; Becerra, Carlos; Fishman, Mayer; Antonia, Scott; Sporn, Michael B.; Liby, Karen T.; Rawal, Bhupendra; Lee, Ji Hyun; Gabrilovich, Dmitry I.

doi:10.1158/1078-0432.ccr-09-3272

Cited by 253 publications

(212 citation statements)

References 41 publications

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“…Nonetheless, the decrease in MDSC numbers was accompanied by improved tumor growth control under autochthonous conditions, spontaneous metastasis, or implantable conditions when combined with an additional anti-MDSC strategy or an immunotherapy. These data are consistent with other studies showing that immune-based therapies mediate stronger antitumor effects when combined with strategies that eliminate MDSCs or inhibit their pro-tumor behavior (44)(45)(46)(47).…”

Section: Figuresupporting

confidence: 92%

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

et al. 2013

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Myeloid-derived suppressor cells (MDSCs IntroductionA major barrier to effective cancer immunotherapy is immune suppression, and the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism to promote immune suppression (1, 2). MDSCs comprise a mixture of myeloid cells reflecting various stages of differentiation, and in mouse models, these cells are typically distinguished from other inhibitory myeloid populations based on their unique coexpression of macrophage (CD11b) and granulocyte (Gr-1) markers (1).Tumor-induced MDSCs are further dichotomized into monocytic and granulocytic subsets based on the differential expression of the Ly6G and Ly6C epitopes (3, 4). Intriguingly, granulocytic MDSCs outnumber monocytic MDSCs in numerous mouse tumor models (3, 5), although the basis for this subset dichotomy remains unclear. The phenotypes in humans are more complex and vary with tumor type. However, there is general agreement that a common lineage-negative MDSC subset observed among a range of human cancers bears the core phenotype CD33 + HLA-DR -(6-11). Interestingly, this subset resembles promyelocytes, a granulocytic population reflecting an early stage of differentiation (6, 7).Although many studies have been dedicated to the phenotypic characterization of MDSCs and unraveling mechanisms by which these cells mediate tumor progression, a large gap remains in our understanding of the mechanisms that initiate their development. It is known, however, that MDSC subsets emerge in response to tumor-derived factors (TDFs) and the signaling pathways these molecules engage. As a number of TDFs engage the STAT3 or STAT5 signaling pathway, STAT3 or STAT5 activation has been associated with various stages in MDSC biology (1,(12)(13)(14)(15)(16)(17)(18)(19).

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Section: Figuresupporting

confidence: 92%

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

et al. 2013

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“…Both subsets have an elevated level of Arg-1 activity. Nitric oxide and Arg-1 restrain exuberant or novel T-cell responses via a variety of different mechanisms, [37][38][39] by interfering with direct TLR signaling and MyD88-dependent activation of nuclear factor-кB (NF-кB). [40][41][42] In this study, the percentages of both circulating and splenic MDSCs were reduced in patients with ITP compared with healthy control patients.…”

Section: Discussionmentioning

confidence: 99%

High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia

Hou

Feng

Xu³

et al. 2016

Blood

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Key Points• The impaired suppressive function of myeloid-derived suppressor cells plays a role in the pathogenesis of immune thrombocytopenia.• The effect of dexamethasone in correcting dysfunction of myeloid-derived suppressor cells suggests a new therapeutic mechanism of high-dose dexamethasone in patients with immune thrombocytopenia.Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor b was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXMmodulated MDSCs inhibited autologous CD4 1 T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61 1 platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.

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“…Different types of cancers have also been shown to induce high levels of peroxynitrite in their microenvironment, which renders T-cells unresponsive to antigen-specific stimulation [67,68].…”

Section: (Figure 2) Inos Breaks Down L-arginine Into Nitric Oxide (Nmentioning

confidence: 99%

Myeloid Derived Suppressor Cells and Their Role in Diseases

Kong¹,

Fuchsberger

Xiang

et al. 2013

CMC

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Abstract:Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitors that can play a major role in tumour development and chronic inflammation. The importance of the suppressive function of MDSCs was first suggested by studies involving cancer patients and cancer-bearing mice. In addition, recent studies have demonstrated that MDSCs can also be involved in many other pathological conditions. MDSCs have unique ways of abrogating an immune response in addition to those utilised by other immune-suppressive cell types, for example via the induction of arginase-1 and consequent upregulation in reactive oxygen species (ROS) production. Due to their heterogeneity, they further can express a variety of lineage markers, which overlap with other myeloid cell types such as Gr1, CD11b, MHCII lo , Ly6C and Ly6G, making it difficult to identify them by surface phenotype alone. The disparity between mouse and human MDSCs further complicates the identification of these elusive cell populations. In this review, we will summarise the recent updates on the methods for eliciting and studying different MDSC subsets, including newly proposed surface phenotypes, as well as insights into how their function is being characterised in both mice and humans. In addition, exciting new discoveries suggesting their involvement across a number of different pathological settings, such as sepsis, autoimmunity and Leishmaniasis, will be discussed.

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Anti-inflammatory Triterpenoid Blocks Immune Suppressive Function of MDSCs and Improves Immune Response in Cancer

Cited by 253 publications

References 41 publications

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis

High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia

Myeloid Derived Suppressor Cells and Their Role in Diseases

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