Monitoring of IL-10 in the serum of patients with advanced ovarian cancer: Results from a prospective pilot-study

Mustea, Alexander; Braicu, Elena Ioana; Koensgen, Dominique; Yuan, Shengguang; Sun, Pengming; Stamatian, Florin; Lichtenegger, W.; Chen, Frank Chih-Kang; Chekerov, Radoslav; Sehouli, Jalid

doi:10.1016/j.cyto.2008.10.019

Cited by 28 publications

(23 citation statements)

References 14 publications

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“…Importantly, IL-10 levels in both serum and ascites correlate with advanced disease and drop significantly after de-bulking surgery [7, 27]. Several cell types within the OC environment secrete IL-10, with TAM and regulatory T cells being major contributors [6, 28].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 and prostaglandin E2 have complementary but distinct suppressive effects on Toll-like receptor-mediated dendritic cell activation in ovarian carcinoma

et al. 2017

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Dendritic cells (DC) have the potential to instigate a tumour-specific immune response, but their ability to prime naïve lymphocytes depends on their activation status. Thus, for tumour immunotherapy to be effective, the provision of appropriate DC activation stimuli such as Toll-like receptor (TLR) agonists is crucial in order to overcome immunosuppression associated with the tumour microenvironment. To address this, we investigated how ovarian carcinoma (OC)-associated ascites impedes activation of DC by TLR agonists. Our results show that ascites reduces the TLR-mediated up-regulation of CD86 and partially inhibits the production of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-12 and tumour necrosis factor α (TNFα) in monocyte-derived DC from healthy controls. We further observe an impaired T cell stimulatory capacity of DC upon activation with TLR agonists in the presence of ascites, indicating that their functionality is affected by the immunosuppressive factors. We identify IL-10 and prostaglandin E2 (PGE2) as the pivotal immunosuppressive components in OC-associated ascites compromising TLR-mediated DC activation. Interestingly, IL-10 is present in both ascites from patients with malignant OC and in peritoneal fluid from patients with benign ovarian conditions and both fluids have similar ability to reduce TLR-mediated DC activation. However, depletion of IL-10 from ascites revealed that the presence of paracrine IL-10 is not crucial for ascites-mediated suppression of DC activation in response to TLR activation. Unlike IL-10, PGE2 is absent from peritoneal fluid of patients with benign conditions and selectively reduces TNFα induction in response to TLR-mediated activation in the presence of OC-associated ascites. Our study highlights PGE2 as an immunosuppressive component of the malignant OC microenvironment rendering PGE2 a potentially important target for immunotherapy in OC.

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Section: Discussionmentioning

confidence: 99%

Interleukin-10 and prostaglandin E2 have complementary but distinct suppressive effects on Toll-like receptor-mediated dendritic cell activation in ovarian carcinoma

et al. 2017

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“…4 The cytokines identified in the present study as being mainly responsible for the induction of GrB in pDCs, namely IL-3 and IL-10, can also be detected in the environment of neoplastic diseases. 11,44,45 This suggests that GrBsecreting pDCs in such an environment could be involved in suppressing the expansion of tumor-specific T cells. Clearly, further studies are needed to investigate whether the regulatory effects of GrB-secreting pDCs on T cells may play a role for immune evasion of such neoplastic diseases.…”

Section: Discussionmentioning

confidence: 99%

Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion

Jahrsdörfer

Vollmer

Blackwell

et al. 2010

Blood

145

136

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Human plasmacytoid dendritic cells (pDCs) are crucially involved in the modulation of adaptive T-cell responses in the course of neoplastic, viral, and autoimmune disorders. In several of these diseases elevated extracellular levels of the serine protease granzyme B (GrB) are observed. Here we demonstrate that human pDCs can be an abundant source of GrB and that such GrB ؉ pDCs potently suppress T-cell proliferation in a GrBdependent, perforin-independent manner, a process reminiscent of regulatory T cells. Moreover, we show that GrB expression is strictly regulated on a transcriptional level involving Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and STAT5 and that interleukin-3 (IL-3), a cytokine secreted by activated T cells, plays a central role for GrB induction. Moreover, we find that the immunosuppressive cytokine IL-10 enhances, while Toll-like receptor agonists and CD40 ligand strongly IntroductionPlasmacytoid dendritic cells (pDCs) represent a central link between innate and adaptive immunity and play a crucial role in viral, autoimmune, and neoplastic diseases. [1][2][3][4] One of their most prominent features is the ability of pDCs to produce and secrete large amounts of type I interferons (IFNs), thereby initiating and orchestrating antiviral immune responses. 1,5 pDCs can also function as antigen-presenting cells and stimulate effector T-cell responses. 6 However, pDC effects on T-cell subsets can include both T-cell activation (immunogenic function) 7 and induction of T-cell anergy (tolerogenic function). 7,8 pDCs therefore play an important role in fine-tuning cellular immune responses depending on the microenvironment. Several studies suggest that both the activated T cell-derived cytokine interleukin-3 (IL-3) 9 and the immunosuppressive cytokine IL-10 induce a rather tolerogenic pDC phenotype associated with suppression of T-cell responses. [10][11][12] In contrast, activation of pDCs in the presence of ligands for the pDC-characteristic Toll-like receptors (TLRs) TLR7 and TLR9 1 and for CD40 10 results in an immunogenic phenotype with such pDC triggering a proinflammatory immune response including T-cell activation and cytotoxicity. 6,13,14 Several inflammatory diseases including viral and autoimmune diseases have been found to be associated with elevated levels of extracellular granzyme B (GrB). Granzymes including GrB have been found to be locally elevated in bronchoalveolar lavage fluid from patients with chronic allergic asthma and in synovial fluid from patients with rheumatoid arthritis. 15 Infections with cytomegalovirus after renal transplantation, with the dengue fever virus or with HIV, have been associated with high serum levels of GrB. 15 Granzymes such as GrB represent a major constituent of the granules of cytotoxic cells, including cytotoxic T lymphocyte (CTL) and natural killer (NK) cells. The classical function of GrB is induction of apoptosis in target cells recognized by CTLs. 16,17 Evidence is growing that apart from its cytotoxic effec...

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“…The presence of IL-10-producing DCs within tumors is associated with increased Treg populations, which have been implicated in playing a crucial role in the occurrence of tumor-mediated immune escape (36,37). Indeed, increase of IL-10 production in human cancers is correlated with poor prognosis (38,39). We have observed that although lung cancer expresses low levels of IL-10, the main source of this cytokine in the tumor microenvironment is the tumor-infiltrating CD11c + DCs.…”

Section: Discussionmentioning

confidence: 99%

Lung Cancer-Derived Galectin-1 Mediates Dendritic Cell Anergy through Inhibitor of DNA Binding 3/IL-10 Signaling Pathway

Kuo

Hung

Huang

et al. 2011

The Journal of Immunology

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Lung cancer, one of the leading causes of death worldwide, is often associated with a state of immune suppression, but the molecular and functional basis remains enigmatic. Evidence is provided in this paper supporting the role of lung cancer-derived soluble lectin, galectin-1, as a culprit in dendritic cell (DC) anergy. We have shown that galectin-1 is highly expressed in lung cancer cell lines, together with the serum and surgical samples from lung cancer patients. Functionally, lung cancer-derived galectin-1 has been shown to alter the phenotypes of monocyte-derived DCs (MdDCs) and impair alloreactive T cell response, concomitant with the increase of CD4+CD25+FOXP3+ regulatory T cells. The regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. This effect is inhibited by the addition of lactose, which normalizes the phenotypic and functional alterations seen in MdDCs. Of note, significant upregulation of IL-10 was seen in tumor-infiltrating CD11c+ DCs in human lung cancer samples. This was also noted in mice transplanted with lung cancer cells, but not in those receiving tumor cells with galectin-1 knockdown. Furthermore, a significant reduction was noted in lung cancer incidence and in the levels of IL-10–expressing, tumor-infiltrating DCs, in mice receiving galectin-1–silenced tumor cells. These results thus suggest that the galectin-1/IL-10 functional axis may be crucial in lung cancer-mediated immune suppression, and that galectin-1 may serve as a target in the development of lung cancer immunotherapy.

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Monitoring of IL-10 in the serum of patients with advanced ovarian cancer: Results from a prospective pilot-study

Cited by 28 publications

References 14 publications

Interleukin-10 and prostaglandin E2 have complementary but distinct suppressive effects on Toll-like receptor-mediated dendritic cell activation in ovarian carcinoma

Interleukin-10 and prostaglandin E2 have complementary but distinct suppressive effects on Toll-like receptor-mediated dendritic cell activation in ovarian carcinoma

Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion

Lung Cancer-Derived Galectin-1 Mediates Dendritic Cell Anergy through Inhibitor of DNA Binding 3/IL-10 Signaling Pathway

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