Anti‐<scp>IL</scp>‐6 receptor m<scp>A</scp>b eliminates myeloid‐derived suppressor cells and inhibits tumor growth by enhancing <scp>T</scp>‐cell responses

Sumida, Kentaro; Wakita, Daiko; Narita, Yoshinori; Masuko, Kazutaka; Terada, Satoshi; Watanabe, Kazue; Satoh, Takayuki; Kitamura, Hiroyuki; Nishimura, Takashi

doi:10.1002/eji.201142335

Cited by 118 publications

(98 citation statements)

References 53 publications

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“…Although IL-6 has been reported to facilitate the development or accumulation of MDSC (35,40,41), we showed that IL-6 deficiency and blockade of IL-6 activity in vivo had no detectable effect on MDSC in tumor-bearing mice. Indicating that tumor-derived IL-6 was not essential for maintenance of Figure 7.…”

Section: Discussioncontrasting

confidence: 55%

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Tsukamoto

Nishikata

Senju

et al. 2013

Cancer Immunology Research

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Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (T H 1) was significantly attenuated, and impaired T H 1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Furthermore, we found that Gr-1 þ myeloid-derived suppressor cells (MDSC) served as a source of IL-6 in tumor-bearing mice. Adoptive transfer of effector CD4 þ T cells revealed that MDSC-sensitized effector CD4 þ T cells were less potent in mounting antitumor immune responses, although effector T cells generated together with Gr-1 þ cells from tumor-free mice eradicated established tumors. CD8 þ T cells, IFN-g, and MHC-class II expression in host mice were indispensable for the antitumor activity initiated by effector CD4 þ T cells. Despite comparable suppressive activity of IL-6 þ/þ and IL-6 À/À MDSC on primary T-cell activation, transfer of IL-6 þ/þ MDSC, but not IL-6 À/À MDSC, dampened the efficient induction of effector T H 1 cells and counteracted CD4 þ T cell-mediated antitumor immunity including cognate help for CD8 þ T cells in vivo. These findings suggest that, apart from the inhibitory effects on primary T-cell activation, MDSC promote tumor progression by attenuating functional differentiation of tumor-specific CD4 þ T cells into effector T H 1 cells through IL-6 production to promote tumor progression. This novel mode of MDSC-induced tolerance of effector CD4 þ T cells should be considered as the basis for the rational design of effective T cell-mediated antitumor therapies.

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Section: Discussioncontrasting

confidence: 55%

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Tsukamoto

Nishikata

Senju

et al. 2013

Cancer Immunology Research

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“…10,[15][16][17] Differential expression of Ly6C and Ly6G divides CD11b C Gr1 C cells into three distinct MDSC subsets: Ly6G hiLy6C med (granulocytic), Ly6G med Ly6C hi (monocytic), and Ly6G-med Ly6C med (non-monocytic and non-granulocytic). Initially, we compared the frequency of the three subsets in EL4 tumor bearing mice and found Ly6G hi Ly6C med MDSCs were the most prevalent and the other two subsets were equivalent in number.…”

Section: Inverse Correlation In the Number Of Mdscs And Nk Cells In Lmentioning

confidence: 99%

“…Using additional markers, these cells can be further divided into three subsets: Gr1 hi or CD11b C Ly6G hi Ly6C low (granulocytic MDSCs) and Gr1 low or CD11b C Ly6G low Ly6C hi (monocytic MDSCs) and Gr1 int or CD11b C Ly6G int Ly6C int MDSCs (non-monocytic and non-granulocytic MDSCs). 4,10,[15][16][17] MDSC composition is dependent on tumor type as differences of MDSC subset frequency and/or function have been demonstrated between different tumor model systems. 18 As a first defense, NK cells and other innate lymphocytes play an essential role in the inhibition of tumorigenesis, tumor growth, and tumor metastasis.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the myeloid-derived suppressor cell subset regulated by NK cells in malignant lymphoma

et al. 2015

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TNFa, tumor necrosis factor a; VEGF, vascular endothelial growth factor.Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population with the ability to suppress immune responses and are currently classified into three distinct MDSC subsets: monocytic, granulocytic and non-monocytic, and non-granulocytic MDSCs. Although NK cells provide an important first-line defense against newly transformed cancer cells, it is unknown whether NK cells can regulate MDSC populations in the context of cancer. In this study, we initially found that the frequency of MDSCs in non-Hodgkin lymphoma (NHL) patients was increased and inversely correlated with that of NK cells, but not that of T cells. To investigate the regulation of MDSC subsets by NK cells, we used an EL4 murine lymphoma model and found the non-monocytic and non-granulocytic MDSC subset, i.e., Gr1 C CD11b C Ly6G med Ly6C med MDSC, is increased after NK cell depletion. The MDSC population that expresses MHC class II, CD80, CD124, and CCR2 is regulated mainly by CD27 C CD11b C NK cells. In addition, this MDSC subset produces some immunosuppressive cytokines, including IL-10 but not nitric oxide (NO) or arginase. We also examined two subsets of MDSCs (CD14 C HLA-DR ¡ and CD14 ¡ HLA-DR ¡ MDSC) in NHL patients and found that higher IL-10-producing CD14 C HLA-DR ¡ MDSC subset can be seen in lymphoma patients with reduced NK cell frequency in peripheral blood. Our analyses of MDSCs in this study may enable a better understanding of how MDSCs manipulate the tumor microenvironment and are regulated by NK cells in patients with lymphoma.

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“…It has been shown that IL-6 mediated the generation, migration and activation of MDSCs via transcription factor STAT3 [26,33,79]. In mouse tumor models, inhibition of IL-6 and/or IL-6R resulted in the drastic reduction of tumor infiltrating MDSCs and in the inhibition of tumor progression [80].…”

Section: General Characteristic Of Mdscsmentioning

confidence: 99%

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

Umansky

Sevko

2012

Cancer Microenvironment

112

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Tumor progression has been demonstrated to be supported by chronic inflammatory conditions developed in the tumor microenvironment and characterized by the longterm secretion of various inflammatory soluble factors (including cytokines, chemokines, growth factors, reactive oxygen and nitrogen species, prostaglandins etc.) and strong leukocyte infiltration. Among leukocytes infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only strongly inhibit an anti-tumor immune reactions mediated by T cells but also directly stimulate tumorigenesis, tumor growth and metastasis by enhancing neoangiogenesis and creating a suitable environment for the metastatic formation. This review provides an overview of interactions between MDSCs and tumor cells leading to MDSC generation, activation and migration to the tumor site, where they can strongly enhance tumor progression. Better understanding of the MDSC-tumor interplay is critical for the development of new strategies of tumor immunotherapy.

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Anti‐IL‐6 receptor mAb eliminates myeloid‐derived suppressor cells and inhibits tumor growth by enhancing T‐cell responses

Abstract: CD11b+ Gr-1 + immature myeloid cells (

Cited by 118 publications

References 53 publications

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Characterization of the myeloid-derived suppressor cell subset regulated by NK cells in malignant lymphoma

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

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