Interferons and the Immunogenic Effects of Cancer Therapy

Minn, Andy J.

doi:10.1016/j.it.2015.09.007

Cited by 110 publications

(88 citation statements)

References 94 publications

(125 reference statements)

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“…Conversely, high/increased ISG expression has been linked to poor prognosis in more advanced tumors. An interferon-related DNA damage resistance signature (IRDS) has been defined by Weichselbaum and Minn that is associated with chemotherapy, radiation, and most recently, immunotherapy resistance in multiple tumor types, including breast (12, 44–46). Therefore, ISG expression, and subsequently the effect of ISGs on tumor growth, may vary by tumor stage (early vs late).…”

Section: Discussionmentioning

confidence: 99%

“…This effect appears to be most prominent in the early stages of tumor development. The opposite phenotype is seen in advanced, therapy-resistant tumors: evidence of interferon signaling (high ISG levels) is associated with a range of tumor types, including breast, that have escaped chemotherapy, radiation, or immunotherapy (12). Herein, we present evidence of a novel role for PR in mediating transcriptional repression of ISGs.…”

Section: Introductionmentioning

confidence: 99%

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Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Walter

Goodman

Singhal

et al. 2017

Molecular Cancer Research

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The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, interferon-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to interferon treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR’s ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for interferon-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. Interferon activation is a critical early step in nascent tumor recognition and destruction through immune surveillance. As the large majority of breast tumors are PR-positive at the time of diagnosis, PR-dependent downregulation of interferon signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors. Implications: This study highlights a novel transcriptional mechanism through which PR drives breast cancer development and potentially evades the immune system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Walter

Goodman

Singhal

et al. 2017

Molecular Cancer Research

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“…For example, un-phosphorylated STAT1 (U-STAT1) is capable of regulating a set of ISGs that offer some protection against various viruses but rendered cells resistant to chemotherapy and radiation (68,69). Studies in mouse models of arthritis and experimental autoimmune encephalomyelitis (EAE) determined that UStat1 regulated ISGs that are regularly induced later rather than earlier after stimulation with either IFN␥ or IFN␤ (68).…”

Section: Chronic Exposure To Ifn␥ Leads To Adsmentioning

confidence: 99%

Current prospects of type II interferon γ signaling and autoimmunity

Green

Young

Valencia

2017

Journal of Biological Chemistry

141

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Edited by Charles E. SamuelInterferon ␥ (IFN␥) is a pleiotropic protein secreted by immune cells. IFN␥ signals through the IFN␥ receptor, a protein complex that mediates downstream signaling events. Studies into IFN␥ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFN␥ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFN␥ signaling biology and the functional roles of IFN␥ in the autoimmune response.According to the National Institutes of Health, autoimmune diseases (ADs) 3 are one of the top 10 leading causes of death in female children and women in all age groups up to 64 years of age (1). Excess secretion of IFNs has been associated with development of human ADs (2). Interferons (IFNs) comprise a family of proteins classified as type I (IFN-␣, -␤, -⑀, -, and -), type II (IFN-␥, herein IFN␥), and type III (IFN-1-4) that have pleiotropic roles in immunity, cancer biology, and autoimmunity (2). Here, we aim to provide a basic understanding of the functions of the type II IFN␥ and the IFN␥-signaling pathway (hereafter referred to as IFN signaling) in a contextual and timing perspective related to the autoimmune environment and the development of ADs.

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“…Hence, we wanted to substantiate this observation and confirm that ICD underlies the innate and adaptive antitumor responses in OV therapy. We also assessed the relation with IFN signaling pathway, another major determinant of the antiviral immune response (17).…”

Section: Introductionmentioning

confidence: 99%