Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression

Tsukamoto, Hirotake; Fujieda, Koji; Hirayama, Masatoshi; Ikeda, Tokunori; Yuno, Akira; Matsumura, K.; Fukuma, Daiki; Araki, Kimi; Mizuta, Hiroshi; Nakayama, Hideki; Senju, Satoru; Nishimura, Yasuharu

doi:10.1158/0008-5472.can-16-2446

Cited by 51 publications

(62 citation statements)

References 41 publications

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“…Consistently, data from TCGA indicate a clear association of increased IFN‐γ expression in the tumor microenvironment with improved overall survival . In contrast, IL‐6/sIL‐6R signaling is predisposed to redirect the differentiation of CD4 + T cells into IL‐4‐producing Th2‐like cells . These observations also accord with clinical data indicating that dominant Th2 cytokine profiles in patients are associated with unfavorable outcomes .…”

Section: Immune‐modulatory Effects Of Il‐6 Signaling On T Cellssupporting

confidence: 75%

“…In addition to IL‐6, elevated levels of sIL‐6R have been proposed as a poor prognostic factor in patients with certain types of cancer, because they promote IL‐6 stabilization and amplify IL‐6 signaling through protecting IL‐6 from rapid degradation in vivo . sIL‐6R is produced by the shedding of membrane‐bound IL‐6R via proteolytic cleavage mainly in hepatocytes or myeloid cells under inflammatory conditions . This finding was supported by the clinical observation that lower expression of membrane‐bound IL‐6R on tumor‐infiltrating myeloid cells was correlated with poor prognosis, because lower expression of membrane‐bound IL‐6R was likely to reflect the shedding and release of sIL‐6R from CD14 + myeloid cells …”

Section: Il‐6 Signaling As a Poor Prognostic Factormentioning

confidence: 86%

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Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

et al. 2017

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Accompanied by the growing clinical applications of immunotherapy in the treatment of cancer patients, development of novel therapeutic approaches to reverse the immune‐suppressive environment in cancer patients is eagerly anticipated, because the success of cancer immunotherapy is currently limited by immune‐suppressive effects in tumor‐bearing hosts. Interleukin (IL)‐6, a pleotropic proinflammatory cytokine, participates in tumor cell‐autonomous processes that are required for their survival and growth, and is therefore known as a poor prognostic factor in cancer patients. In addition, an emerging role of IL‐6 in modulating multiple functions of immune cells including T cells, dendritic cells, and macrophages is responsible for the dysfunction of innate and adaptive immunity against tumors. Therefore, the IL‐6‐targeting approach is of value as a promising strategy for desensitization and prevention of immune‐suppressive effects, and should be an effective treatment when combined with current immunotherapies. The aim of the present review is to discuss the immune‐suppressive aspects of IL‐6, notably with modification of T‐cell functions in cancer patients, and their relationship to anti‐tumor immune responses and cancer immunotherapy.

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Section: Immune‐modulatory Effects Of Il‐6 Signaling On T Cellssupporting

confidence: 75%

Section: Il‐6 Signaling As a Poor Prognostic Factormentioning

confidence: 86%

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

et al. 2017

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“…The researchers revealed that c‐Maf activity was responsible for IL‐6/sIL‐6R‐induced Th1 suppression and defective T‐cell‐mediated antitumor responses. These data suggest another mechanism for effects of IL‐6 that will directly affect T cell function …”

Section: Other Aspects Of Interleukin‐6 For Anti‐tumor Immunity and Tmentioning

confidence: 84%

“…In fact, a cancer peptide vaccine containing a helper epitope induced CTL in an advanced cancer patient, and the patient experienced a clinical benefit . Recent studies have revealed that IL‐6 produced in tumor environments suppresses the differentiation of IFN‐γ‐producing Th1 cells and promotes subsequent tumor formation . These results suggest that activation of Th1 cells is a crucial event for induction of anticancer immunity in cancer patients.…”

Section: Suppressive Effects Of Interleukin‐6 On Dendritic Cell‐mediamentioning

confidence: 99%

Interleukin‐6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

et al. 2017

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Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

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“…Thus, IL‐6‐mediated STAT3 activation appears to be a critical mechanism to induce dysfunctional immune system responses in the tumor microenvironment through regulation of antigen‐presenting cells. Recent studies have revealed that IL‐6 produced in tumor environments suppresses differentiation of interferon (IFN)‐ γ‐producing helper T cells and promotes subsequent tumor formation . Furthermore, we found that IL‐6 is widely produced and STAT3 is activated in tumor microenvironments of colorectal cancer patients, and the CD11b + CD11c + population isolated from tumor tissues shows higher IL‐6 gene expression compared with the same phenotypic population isolated from PBMC .…”

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confidence: 75%

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

et al. 2017

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Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)‐6, a pleiotropic cytokine, is produced in the tumor‐bearing state. In the present study, we investigated the precise effects of IL‐6 on antitumor immunity and the subsequent tumorigenesis in tumor‐bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild‐type and IL‐6‐deficient mice. As a result, we found that tumor growth was decreased significantly in IL‐6‐deficient mice compared with wild‐type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL‐6‐deficient condition. In addition, higher numbers of interferon (IFN)‐γ‐producing T cells were present in the tumor tissues of IL‐6‐deficient mice compared with wild‐type mice. Surface expression levels of programmed death‐ligand 1 (PD‐L1) and MHC class I on CT26 cells were enhanced under the IL‐6‐deficient condition in vivo and by IFN‐γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti‐PD‐L1 antibody or a Toll‐like receptor 3 ligand, polyinosinic‐polycytidylic acid, effectively inhibited tumorigenesis under the IL‐6‐deficient condition. Based on these findings, we speculate that a lack of IL‐6 produced in tumor‐bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL‐6 signaling may be a promising target for the development of effective cancer immunotherapies.

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Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression

Cited by 51 publications

References 41 publications

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

Interleukin‐6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

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