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Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma.

ABSTRACT: Immunotherapeutic modalities are commonly used for treatment of patients with melanoma. The therapeutic success in preclinical models has not yielded the expected clinical results. To understand this discrepancy, we attempted to define immune homeostasis of 209 patients with melanoma across stages of disease relative to normal controls.Peripheral blood mononuclear cells (PBMC) and plasma were collected from patients and healthy donors. PBMC were analyzed for frequencies of natural killer, dendritic, and T cells and their functional status. Matched plasma samples were analyzed for the concentrations of 27 cytokines, chemokines, and growth factors. RNA was isolated from 24 metastatic melanoma tumor biopsies and profiled by microarray analysis.The frequency of natural killer, T, and dendritic cells in patients does not significantly change across stages of melanoma. However, plasma concentrations of Th2 cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] in tumor-bearing patients were significantly higher than those with resected melanoma. Expression array analysis of metastatic melanoma revealed that the malignant melanocytes were not the source of the Th2 cytokines but did highly up-regulate vascular endothelial growth factor (VEGF) transcripts, consistent with plasma VEGF concentrations. In vitro VEGF exposure of normal PBMC lead to repolarization from Th1 to Th2 emulating the state of metastatic melanoma.Patients with metastatic melanoma exist in a state of Th2-mediated "chronic inflammation" as a result of at least VEGF overproduction by malignant tumors. These data support prior observations regarding the effect of VEGF on immune cell function and suggests consideration of VEGF inhibitors in future cancer immunotherapy clinical studies in metastatic melanoma.

SUBMITTER: Nevala WK

PROVIDER: S-EPMC2757059 | biostudies-other | 2009 Mar

REPOSITORIES: biostudies-other

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Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma.

Nevala Wendy K WK Vachon Celine M CM Leontovich Alexey A AA Scott Christopher G CG Thompson Michael A MA Markovic Svetomir N SN

Clinical cancer research : an official journal of the American Association for Cancer Research 20090224 6

<h4>Purpose</h4>Immunotherapeutic modalities are commonly used for treatment of patients with melanoma. The therapeutic success in preclinical models has not yielded the expected clinical results. To understand this discrepancy, we attempted to define immune homeostasis of 209 patients with melanoma across stages of disease relative to normal controls.<h4>Experimental design</h4>Peripheral blood mononuclear cells (PBMC) and plasma were collected from patients and healthy donors. PBMC were analyz ...[more]

PMID: 19240164

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Project description:BackgroundRecent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This interdisciplinary effort exploits engineering analysis methods utilized to investigate anomalous physical system behaviors to explore immune system behaviors. Cancer Immune Control Dynamics (CICD), a systems analysis approach, attempts to identify differences between systemic immune homeostasis of 27 healthy volunteers versus 14 patients with metastatic malignant melanoma based on daily serial measurements of conventional peripheral blood biomarkers (15 cell subsets, 35 cytokines). The modeling strategy applies engineering control theory to analyze an individual's immune system based on the biomarkers' dynamic non-linear oscillatory behaviors. The reverse engineering analysis uses a Singular Value Decomposition (SVD) algorithm to solve the inverse problem and identify a solution profile of the active biomarker relationships. Herein, 28,605 biologically possible biomarker interactions are modeled by a set of matrix equations creating a system interaction model. CICD quantifies the model with a participant's biomarker data then computationally solves it to measure each relationship's activity allowing a visualization of the individual's current state of immunity.ResultsCICD results provide initial evidence that this model-based analysis is consistent with identified roles of biomarkers in systemic immunity of cancer patients versus that of healthy volunteers. The mathematical computations alone identified a plausible network of immune cells, including T cells, natural killer (NK) cells, monocytes, and dendritic cells (DC) with cytokines MCP-1 [CXCL2], IP-10 [CXCL10], and IL-8 that play a role in sustaining the state of immunity in advanced cancer.ConclusionsWith CICD modeling capabilities, the complexity of the immune system is mathematically quantified through thousands of possible interactions between multiple biomarkers. Therefore, the overall state of an individual's immune system regardless of clinical status, is modeled as reflected in their blood samples. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.

Project description:ObjectiveAccumulating evidence links juvenile idiopathic arthritis (JIA) to nonhost factors such as gut microbes. We hypothesize that children with new-onset JIA have increased intestinal bacterial translocation and circulating lipopolysaccharide (LPS).MethodsWe studied systemic treatment-naive patients with JIA [polyarticular JIA, n = 22, oligoarticular JIA, n = 31, and spondyloarthropathies (SpA), n = 16], patients with established inflammatory bowel disease-related arthritis (IBD-RA, n = 11), and 34 healthy controls. We determined circulating IgG reactivity against LPS, LPS-binding protein (LBP), α-1-acid glycoprotein (α-1AGP), and C-reactive protein (CRP) in plasma or serum from these patients and controls. Juvenile Arthritis Disease Activity Score (JADAS-27) was calculated for patients with JIA.ResultsCirculating anticore LPS antibody concentrations in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.024), and SpA (p = 0.001) were significantly greater than in controls, but there were no significant intergroup differences. Circulating LBP concentrations were also significantly greater in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.002), and SpA (p = 0.006) than controls, as were α-1AGP concentrations (p = 0.001, 0.001, and 0.003, respectively). No differences were observed between controls and patients with IBD-RA in any of the assays. Circulating concentrations of LBP and α-1AGP correlated strongly with CRP concentrations (r = 0.78 and r = 0.66, respectively). Anticore LPS antibody levels and CRP (r = 0.26), LBP (r = 0.24), and α-AGP (r = 0.22) concentrations had weaker correlations. JADAS-27 scores correlated with LBP (r = 0.66) and α-1AGP concentrations (r = 0.58).ConclusionChildren with polyarticular JIA, oligoarticular JIA, and SpA have evidence of increased exposure to gut bacterial products. These data reinforce the concept that the intestine is a source of immune stimulation in JIA.

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Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma.

Publications

Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma.

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