STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients

Vasquez-Dunddel, David; Fan, Ping; Zeng, Qi; Gorbounov, Mikhail; Albesiano, Emilia; Fu, Juan; Blosser, Richard L.; Tam, Ada; Bruno, Tullia C.; Zhang, Hao; Pardoll, Drew M.; Kim, Young

doi:10.1172/jci60083

Cited by 457 publications

(452 citation statements)

References 53 publications

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“…CD14 1 HLA-DR 2/low cells express STAT3 and pSTAT3 associated with increased CCL2 A previous study showed that STAT3 signaling plays an important role in CD14 1 HLA-DR 2/low MDSCs expansion 24 . We examined whether STAT3 signaling was also involved in the expansion of CD14 1 HLA-DR 2/low MDSCs through crosstalk between CD14 1 myelomonocytic cells and trophoblast cells and whether CCL2 mediates this process.…”

Section: Resultsmentioning

confidence: 93%

Human trophoblast cells induced MDSCs from peripheral blood CD14+ myelomonocytic cells via elevated levels of CCL2

Zhang

Sun

et al. 2015

Cell Mol Immunol

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Successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus. Myeloid-derived suppressor cells (MDSCs), which are capable of inhibiting T-cell responses, are highly increased in the early stages of pregnancy. Although recent reports indicate a role for MDSCs in fetal-maternal tolerance, little is known about the expansion of MDSCs during pregnancy. In the present study, we demonstrated that the trophoblast cell line HTR8/SVneo could instruct peripheral CD14 1 myelomonocytic cells toward a novel subpopulation of MDSCs, denoted as CD14 1 HLA-DR 2/low cells, with suppressive activity and increased expression of IDO1, ARG-1, and COX2. After interaction with HTR8/SVneo cells, CD14 1 myelomonocytic cells secrete high levels of CCL2, promoting the expression of signal transducer and activator of transcription 3. We utilized a neutralizing monoclonal antibody to reveal the prominent role of CCL2 in the induction of CD14 1 HLA-DR 2/low MDSCs. In combination, the results of the present study support a novel role for the cross-talk between the trophoblast cell line HTR8/SVneo and maternal CD14 1 myelomonocytic cells in initiating MDSCs induction, prompting a tolerogenic immune response to ensure a successful pregnancy. Cellular & Molecular Immunology

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Section: Resultsmentioning

confidence: 93%

Human trophoblast cells induced MDSCs from peripheral blood CD14+ myelomonocytic cells via elevated levels of CCL2

Zhang

Sun

et al. 2015

Cell Mol Immunol

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“…Interestingly, there appears to be a consensus regarding activation of Janus kinase protein and STAT 3 and 5 (47). Indeed, some reports argue that STAT 3 and 5 regulate MDSC function in both mice and humans (9,10,48 (20). Thus, these findings appear to be important in terms of MDSC induction by mTOR inhibitors or other immunosuppressive drugs in the context of clinical organ transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it would be interesting to examine the mechanisms by which MDSCs suppress immunological rejection and to identify the specific molecules involved; such knowledge could then be applied to clinical organ transplantation. Intensive research on MDSCs has shed light on the factors that influence their kinetics and function (8)(9)(10)(11). However, the exact mechanisms by which MDSCs suppress immune responses are unclear.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

Nakamura

Nakao

Yoshimura

et al. 2015

American Journal of Transplantation

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Mammalian target of rapamycin (mTOR) inhibitors are the main immunosuppressive drugs for organ transplant recipients. Nevertheless, the mechanisms by which mTOR inhibitors induce immunosuppression is not fully understood. Myeloid‐derived suppressor cells (MDSCs) maintain host immunity; however, the relationship between mTOR inhibitors and MDSCs is unclear. Here, the results from a murine cardiac transplantation model revealed that rapamycin treatment (3 mg/kg, intraperitoneally on postoperative days 0, 2, 4, and 6) led to the recruitment of MDSCs and increased their expression of inducible nitric oxide synthase (iNOS). Immunohistochemical analysis revealed that rapamycin induced the migration of iNOS‐expressing MDSCs into the subintimal space within the allograft vessels, resulting in a significant prolongation of graft survival compared with that in the untreated group (67 days vs. 7 days, respectively). These effects were counterbalanced by the administration of an anti‐Gr‐1, which reduced allograft survival to 21 days. Moreover, adoptive transcoronary arterial transfer of MDSCs from rapamycin‐treated recipients prolonged allograft survival; this increase was reversed by the anti‐Gr‐1 antibody. Finally, co‐administration of rapamycin and a mitogen‐activated protein kinase kinase (MEK) inhibitor trametinib reversed rapamycin‐mediated MDSC recruitment. Thus, the mTOR and Raf/MEK/extracellular signal regulated kinase (ERK) signaling pathways appear to play an important role in MDSC expansion.

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“…Furthermore, the ability of MDSCs to suppress T-cell proliferation may be central to tumor formation (43)(44)(45). ARG-1-mediated depletion of L-arginine, ROS production, and STAT3 activation regulate the functions of MDSCs and have been reported to be the mechanisms responsible for the ability of MDSC to suppress T-cell functions (29)(30)(31). Through FACS analysis using murine spleen tissues, we demonstrated that calcitriol attenuated the increases in the levels of ROS, activated STAT3 and suppressive ability of T-cell proliferation in MDSCs obtained from IL6-stimulated or 4-NQOtreated mice.…”

Section: Discussionmentioning

confidence: 99%

“…6A, calcitriol abrogated the recruitment of MDSCs induced by IL6 stimulation in C57 mice. MDSCs are a heterogeneous cell population characterized by the ability to suppress T-cell functions including proliferation via a range of mechanisms, including reactive oxygen species (ROS) production and increases in the activated STAT3 levels (28)(29)(30)(31). Therefore, to further assess whether calcitriol treatment impaired the function of the recruited MDSCs, we examined the levels of p-STAT3 and ROS and the suppressive ability of Tcell proliferation in MDSCs from IL6-stimulated or 4-NQOtreated mice with or without calcitriol treatment.…”

Section: Effects Of Calcitriol On the Recruitment And Function Of Mdsmentioning

confidence: 99%

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

Chen

Hsieh

et al. 2015

Molecular Cancer Therapeutics

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The aim of this study was to highlight the role of 1a,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQOinduced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D 3 may be a promising strategy for the prevention and treatment of esophageal SCC.

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STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients

Abstract: Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types

Cited by 457 publications

References 53 publications

Human trophoblast cells induced MDSCs from peripheral blood CD14+ myelomonocytic cells via elevated levels of CCL2

Human trophoblast cells induced MDSCs from peripheral blood CD14+ myelomonocytic cells via elevated levels of CCL2

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

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