Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment

Katlinski, Kanstantsin V.; Gui, Jun; Katlinskaya, Yuliya; Ortiz, Angélica; Chakraborty, Riddhita; Bhattacharya, Sabyasachi; Carbone, Christopher J.; Beiting, Daniel P.; Girondo, Melanie A.; Peck, Amy R.; Puré, Ellen; Chatterji, Priya; Rustgi, Anil K.; Diehl, J. Alan; Koumenis, Constantinos; Rui, Hallgeir; Fuchs, Serge Y.

doi:10.1016/j.ccell.2017.01.004

Cited by 196 publications

(212 citation statements)

References 55 publications

(75 reference statements)

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“…Mice lacking IFNAR, the IFNα-binding receptor that initiates JAK/STAT-signaling which culminates in ISG transcription, have enhanced tumor development, impaired ability to reject syngeneic/allogenic tumors, and accelerated metastasis in a spontaneous mouse mammary gland tumor model (39, 40). A recent report shows that IFNAR inactivation in tumor-associated stroma leads to an immune-privileged niche for developing colon cancers (41). Type I interferons, in particular, and dendritic cells have been shown to be critical to tumor cell rejection, and therefore immune surveillance (42).…”

Section: Discussionmentioning

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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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%

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

Walter

Goodman

Singhal

et al. 2017

Molecular Cancer Research

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“…Nevertheless, loss of one copy of IFN-γ, a type II interferon in the background of Apc min/+ mice demonstrated faster progression to colonic adenocarcinoma, through elevated expression of Wnt2 and elevated levels of activated EGFR and ERK1/2 [35]. A mechanism by which CRC cells evade the tumoricidal effects of interferon signaling is through downregulation of type I interferon receptor chain IFNAR1, which limits the therapeutic response of anti-PD1 therapy, an immune checkpoint inhibitor [36]. Infra S526A mice, which are deficient in ubiquitination and proteasomal degradation of INFAR1, exhibited a significant reduction in tumor number and prolonged survival compared to wildtype controls in CAC.…”

Section: Inflammatory Signaling Pathways In Colorectal Cancer: Insighmentioning

confidence: 99%

Inflammation and Colorectal Cancer

Long

Lundsmith

Hamilton

2017

Curr Colorectal Cancer Rep

141

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Colorectal cancer (CRC) is the fourth most common cancer in both men and women in the United States, resulting in over 55,000 deaths annually. Environmental and genetic factors influence the development of CRC, and inflammation is a critical hallmark of cancer that may arise from a variety of factors. Purpose of review While patients with inflammatory bowel disease (IBD) have a higher risk of developing CRC, sporadic CRCs may engender or be potentiated by inflammation as well. In this review, we focus on recent advances in basic and translational research utilizing murine models to understand the contribution of inflammatory signaling pathways to CRC. Recent findings We discuss advances in the utility of three-dimensional enteroid/colonoid/tumoroid cultures to understand immune-epithelial interactions in CRC, as well as the potential for utilizing patient-derived tumoroids for personalized therapies. Summary This review underscores the importance of understanding the complex molecular mechanisms underlying inflammation in sporadic CRC and highlights up-and-coming or new avenues for CRC biomarkers or therapies.

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“…74 It is widely believed that tumour-derived EVs impose significant effects in mediating communication between immune and cancer cells of renal cell cancer (RCC), 75 such as immune evasion of tumours. 76,77 MiR-222-3p induces polarization of tumour-associated macrophages by the activation of SOCS3/ STAT3 pathway to facilitate tumourigenesis and cancer progression. 78 Additionally, Rab27a supports exosome could modify the tumour microenvironment via advancing recruitment and differentiation of bone marrow-derived neutrophils to cancer cells.…”

Section: Modul Ation Of the Tumour Microenvironmentmentioning

confidence: 99%

Extracellular vesicles in urologic malignancies—Implementations for future cancer care

Zhang

Xia

et al. 2019

Cell Proliferation

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Extracellular vesicles (EVs), a heterogeneous group of vesicles differing in size and shape, cargo content and function, are membrane‐bound and nano‐sized vesicles that could be released by nearly all variations of cells. EVs have gained considerable attention in the past decades for their functions in modulating intercellular signalling and roles as potential pools for the novel diagnostic and prognostic biomarkers, as well as therapeutic targets in several cancers including urological neoplasms. In general, human and animal cells both can release distinct types of EVs, including exosomes, microvesicles, oncosomes and large oncosomes, and apoptotic bodies, while the content of EVs can be divided into proteins, lipids and nucleic acids. However, the lack of standard methods for isolation and detection platforms rein the widespread usage in clinical applications warranted furthermore investigations in the development of reliable, specific and sensitive isolation techniques. Whether and how the EVs work has become pertinent issues. With the aid of high‐throughput proteomics or genomics methods, a fully understanding of contents contained in EVs from urogenital tumours, beyond all doubt, will improve our ability to identify the complex genomic alterations in the process of cancer and, in turn, contribute to detect potential therapeutic target and then provide personalization strategy for patient.

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Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment

Cited by 196 publications

References 55 publications

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

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

Inflammation and Colorectal Cancer

Extracellular vesicles in urologic malignancies—Implementations for future cancer care

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