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Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma.

ABSTRACT: Background:Interferons (IFNs) are cytokines typically induced upon viral infection but are constitutively expressed also in the absence of acute infection. The physiological role of autocrine and paracrine IFN signaling, however, remains poorly understood, and its function in glioblastoma has not been explored in depth. Methods:Using RNA interference-mediated gene silencing, we characterized constitutive type I IFN signaling and its role in human glioma cells. Results:We observed constitutive expression of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and myxovirus resistance protein A (MxA), a classical IFN-response marker, in the absence of exogenous IFN-?. In vivo, we found higher MxA expression in gliomas than in normal tissue, suggesting that IFN signaling is constitutively active in these tumors. To demonstrate the presence of an autocrine type I IFN signaling loop in glioma cells in vitro, we first confirmed the expression of the type I alpha/beta receptor (IFNAR)1/2, and its ligands, IFN-? and IFN-?. Small interfering RNA-mediated receptor gene silencing resulted in reduced expression of MxA at mRNA and protein levels, as did gene silencing of the ligands, corroborating the hypothesis of an autocrine signaling loop in which type I IFNs induce intracellular signaling through IFNAR1/2. On a functional level, following IFNAR1 or IFNAR2 gene silencing, we observed reduced programmed death ligand 1 (PD-L1) and major histocompatibility complex (MHC) class I and II expression as well as an enhanced susceptibility to natural killer immune cell lysis, suggesting that autocrine IFN signaling contributes to the immune evasion of glioma cells. Conclusions:Our findings point to an important role of constitutive IFN signaling in glioma cells by modulating their interaction with the microenvironment.

SUBMITTER: Silginer M

PROVIDER: S-EPMC5596176 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma.

Silginer Manuela M Nagy Sara S Happold Caroline C Schneider Hannah H Weller Michael M Roth Patrick P

Neuro-oncology 20171001 10

<h4>Background</h4>Interferons (IFNs) are cytokines typically induced upon viral infection but are constitutively expressed also in the absence of acute infection. The physiological role of autocrine and paracrine IFN signaling, however, remains poorly understood, and its function in glioblastoma has not been explored in depth.<h4>Methods</h4>Using RNA interference-mediated gene silencing, we characterized constitutive type I IFN signaling and its role in human glioma cells.<h4>Results</h4>We ob ...[more]

PMID: 28475775

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Project description:PurposeCyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.Experimental designParental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.ResultsParental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.ConclusionsAberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.

Project description:Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers, TGF-β exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-β are not fully understood. The present study validates the role of TGF-β signaling in cancer progression and explores mediators of pro-oncogenic TGF-β activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-β receptors decreased both basal and TGF-β-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-β stimulation of cell motility and invasion. TGF-β disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-β. Blockade of Raf-MEK signaling enhanced TGF-β induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-β rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-β stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-β receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-β signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-β-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-β signaling.

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Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma.

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Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma.

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