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Characterization of cytokinome landscape for clinical responses in human cancers.

ABSTRACT: Dysfunctional intratumoral immune reactions are shaped by complex networks of cytokines (including chemokines), and how the cytokinome landscape coordinates with tumors has not been systematically investigated. Using high-dimensional datasets of cancer specimens, we explored the transcript abundance, biomarker potential, and prognostic impact of local cytokines across 19 tumor types. We found that most cytokines are highly locally dysregulated (p = 0.024), revealing spatiotemporal pattern of local cytokines in the development of cancers. In addition, we noted the significant downregulation of CCL14 and CXCL12 in 9 and 10 cancer types, respectively, implying their crucial roles in tumor pathogenesis. We also found that cytokines showed significantly higher specificity properties compared to other protein-coding genes (PCGs) in primary tumor specimens (p << 0.001), indicating that tissue context remains an issue when considering cancer cytokinomes. Finally, we linked concentrations of local cytokines to patient survival. Our results thus provide a panoramic view of pan-cancer cytokinomes, which highlights tumor type specificity of cancer-related cytokines and their impacts on disease prognosis.

SUBMITTER: Wong HS

PROVIDER: S-EPMC5139633 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Characterization of cytokinome landscape for clinical responses in human cancers.

Wong Henry Sung-Ching HS Chang Che-Mai CM Liu Xiao X Huang Wan-Chen WC Chang Wei-Chiao WC

Oncoimmunology 20161104 11

Dysfunctional intratumoral immune reactions are shaped by complex networks of cytokines (including chemokines), and how the cytokinome landscape coordinates with tumors has not been systematically investigated. Using high-dimensional datasets of cancer specimens, we explored the transcript abundance, biomarker potential, and prognostic impact of local cytokines across 19 tumor types. We found that most cytokines are highly locally dysregulated (<i>p</i> = 0.024), revealing spatiotemporal pattern ...[more]

PMID: 27999736

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Project description:UnlabelledCytokines are a group of small secreted proteins that mediate a diverse range of immune and nonimmune responses to inflammatory and microbial stimuli. Only a few of these cytokines mount an antiviral response, including type I, II, and III interferons (IFNs). During viral infections and under inflammatory conditions, a number of cytokines and chemokines are coproduced with IFN; however, no systematic study exists on the interactions of the cytokine repertoire with the IFN response. Here, we performed the largest cytokine and chemokine screen (the human cytokinome, with >240 members) to investigate their modulation of type I and type II IFN responses in a cell line model. We evaluated the cytokine activities in both IFN-stimulated response element (ISRE) and IFN-? activation sequence (GAS) reporter systems. Several cytokine clusters that augment either or both ISRE- and GAS-mediated responses to IFNs were derived from the screen. We identified novel modulators of IFN response-betacellulin (BTC), interleukin 11 (IL-11), and IL-17F-that caused time-dependent induction of the IFN response. The ability to induce endogenous IFN-? and IFN-stimulated genes varies among these cytokines and was largely dependent on Stat1, as assessed by Stat1 mutant fibroblasts. Certain cytokines appear to augment the IFN-? response through the NF-?B pathway. The novel IFN-like cytokines augmented the antiviral activity of IFN-? against several RNA viruses, including encephalomyocarditis virus, vesicular stomatitis virus, and influenza virus, in susceptible cell lines. Overall, the study represents a large-scale analysis of cytokines for enhancing the IFN response and identified cytokines capable of enhancing Stat1, IFN-induced gene expression, and antiviral activities.ImportanceInnate immunity to viruses is an early defense system to ward off viruses. One mediator is interferon (IFN), which activates a cascade of biochemical events that aim to control the virus life cycle. In our work, we examined more than 200 cytokines, soluble mediators produced within the body as a result of infection, for the ability to enhance IFN action. We identified enhanced interactions with specific IFNs and cytokines. We also revealed that betacellulin, IL-17, and IL-11 cytokines have the novel property of enhancing the antiviral action of IFN against several viruses. These results demonstrate that the human genome codes for previously unknown proteins with unrelated functions that can augment the innate immunity to viruses. Knowing these interactions not only helps our understanding of immunity to viruses and emerging diseases, but can also lead to devising possible new therapeutics by enhancing the mediator of antiviral action itself, IFN.

Dataset Information

Characterization of cytokinome landscape for clinical responses in human cancers.

Publications

Characterization of cytokinome landscape for clinical responses in human cancers.

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