Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

Wouters, Maartje C.A.; Dijkgraaf, Eveline M.; Kuijjer, Marieke L.; Jordanova, Ekaterina S.; Hollema, Harry; Welters, Marij J.P.; Hoeven, J. van der; Daemen, Toos; Kroep, Judith R.; Nijman, HW; Burg, Sjoerd van der

doi:10.4161/21624011.2014.962397

Cited by 27 publications

(24 citation statements)

References 40 publications

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“…Prostaglandin E 2 and IL6 are associated with the tumor-induced differentiation of TAMs and with chemotherapy resistance (31,32). In addition, IL6-expressing ovarian cancer cells were associated with dense infiltration by CD163 þ myeloid cells, including TAMs (33). Although IL6 promotes tumor cell proliferation and angiogenesis in some cancers (34), we did not observe increased invasion or proliferation of LLC IL6 cells in vitro.…”

Section: Discussioncontrasting

confidence: 40%

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

et al. 2016

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Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs. Cancer Res; 76(2); 358-69. Ó2015 AACR.

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Section: Discussioncontrasting

confidence: 40%

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

et al. 2016

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“…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: 78%

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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“…The exact mechanism behind this hematologic paraneoplastic manifestation is unclear but is most likely caused by tumor-produced hematopoietic cytokines ( e.g. GM-CSF, G-CSF, IL-6, PGE2) 13 , 29 that are known to mobilize and expand MDSC and macrophages from the bone marrow. 30 In line with our previous studies in lung and cervical cancer, 26 , 31 these myeloid cells are suppressive since in vitro depletion unleashed T cell reactivity to recall antigens and tumor antigens.…”

Section: Discussionmentioning

confidence: 99%

“…CD8+ T cell infiltration into EOC has a positive effect on chemotherapy response, 7 , 8 while infiltration with suppressive immune cells such as regulatory T cells (Tregs), myeloid derived suppressor cells (MDSC) and M2 macrophages is associated with a lower response to chemotherapy in EOC. 10-13 In addition, a strong influx of MDSC in ascites is associated with poor survival. 14 Furthermore, EOC causes systemic suppression of CD8+ T cell reactivity 15 and abnormal high levels of leukocytes (i.e.…”

Section: Introductionmentioning

confidence: 99%

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

et al. 2018

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Epithelial ovarian cancer (EOC) may cause abnormal blood levels of leukocytes. This paraneoplastic manifestation is associated with a worse response to therapy and shorter survival. To understand the complexity and nature of these leukocytes, we dissected the different populations of myeloid cells and analyzed their relation to clinical outcome. Therefore, baseline blood samples of 36 EOC patients treated either with carboplatin/doxorubucin or with gemcitabine were analyzed for different subsets of monocytes/macrophages, myeloid derived suppressor cells (MDSC) and dendritic cells (DC) using multiparameter flow cytometry as well as functional assays for myeloid cell mediated suppression of antigen-specific T cell reactivity. Healthy donor blood served as control. EOC patients displayed an increase in monocytes/macrophages, monocytic MDSC (mMDSC) and CD33-CD11b+CD14-CD15- double-negative MDSC (CD33- dnMDSC) and a decrease in the frequency of DC, across all EOC subtypes. A low frequency of DC and high frequencies of monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were associated with poor overall survival. Patient's monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were shown to suppress T cell reactivity in vitro. The mMDSC and DC frequencies were not altered upon treatment. Importantly, the mMDSC to DC ratio was the strongest independent, highly sensitive and specific, predictive factor for survival. This was irrespective of the type of chemotherapy or disease stage and outperformed classical parameters as WHO status or time from last chemotherapy. Thus, the baseline blood mMDSC to DC ratio is a robust, independent and easy to analyze predictive factor for EOC survival, and may assist patient selection for immunotherapy.

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Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

Cited by 27 publications

References 40 publications

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

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

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

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