Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss

Liu, Huayang; Golji, Javad; Brodeur, Lauren K.; Chung, Franklin; Chen, Julie T.; DeBeaumont, Rosalie; Bullock, Caroline; Jones, Michael D.; Kerr, Gráinne; Li, Li; Rakiec, Daniel P.; Schlabach, Michael R.; Sovath, Sosathya; Growney, Joseph D.; Pagliarini, Raymond; Ruddy, David A.; MacIsaac, Kenzie D.; Korn, Joshua M.; McDonald, Ellice

doi:10.1038/s41591-018-0302-5

Cited by 275 publications

(327 citation statements)

References 48 publications

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“…This concept bases on the notion that the provision of high-dose ligands from an outside source may activate RIG-I signaling to a greater extent than endogenous ligands in the tumor microenvironment, thus generating high-level immunity and overcoming immunosuppression and exhaustion. 17,55 In addition, RIG-I-expressing (ISG signature-positive) tumors may be susceptible to the loss of ADAR1, 31 which may offer new therapeutic prospects in a subset of patients.…”

Section: Discussionmentioning

confidence: 99%

“…We next investigated the expression of the interferonstimulated genes (ISGs) and double-stranded RNA-editing enzymes ADAR1 and ADAR2, the former of which is critically required for cancer cell survival in ISG signaturepositive tumors. 31,32 RIG-I levels correlated significantly with ADAR1 expression (p < 0.001, Fig. 4e) but were less strongly associated with ADAR2 expression (p = 0.043, Fig.…”

Section: Rig-i Marks Immunosuppression In the Tumor Microenvironmentmentioning

confidence: 97%

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High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

Wolf

Fiegl

Zeimet

et al. 2019

Intl Journal of Cancer

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Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum‐based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real‐time quantitative PCR to assess the expression of retinoic acid‐inducible gene‐I (RIG‐I) in primary tumor and healthy ovarian control tissues. RIG‐I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG‐I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG‐I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type‐II cancers and cancers with inactivating p53 mutations exhibited higher RIG‐I expression. RIG‐I levels were also elevated in cancers that recurred after remission or were platinum‐refractory. Survival analyses disclosed RIG‐I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG‐I expression in the tumor microenvironment, including interferon production and a distinct immune‐regulatory signature involving checkpoint molecules (PD‐L1/PD‐1), the RNA‐editing enzyme ADAR1 and the regulatory T cell‐specific transcription factor FoxP3. We conclude that high RIG‐I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG‐I expression may inform checkpoint blockade and/or RIG‐I agonistic targeting in a subset of high‐risk OC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Rig-i Marks Immunosuppression In the Tumor Microenvironmentmentioning

confidence: 97%

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

Wolf

Fiegl

Zeimet

et al. 2019

Intl Journal of Cancer

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“…A recent study demonstrated that cancer cells exhibit high ISG expression due to chronic IFN signaling sustained by the STING adaptor protein, which is activated by various intracellular nucleic acid sensors (60,61). Thus, elevated ISG expression in cancer cells could be attributed to the accumulation of cytosolic double-stranded DNA, which may arise from the disruption of micronuclei as a result of DNA damage, chromosome mis-segregation, and chromothripsis (62,63).…”

Section: Discussionmentioning

confidence: 99%

ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer

Somerville

et al. 2019

Preprint

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ClassificationBIOLOGICAL SCIENCES: Cell Biology. KeywordsZBED2, IRF1, interferon, lineage plasticity, pancreatic ductal adenocarcinoma ABSTRACT Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease.Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of interferon-stimulated genes, which occurs through antagonism of Interferon Regulatory Factor 1 (IRF1)-mediated transcriptional activation at co-occupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of interferon signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the interferon response pathway and to promote lineage plasticity in this disease.

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“…Expression of an interferon-stimulated gene (ISG) signature 21 was similar between primary and transplant tumors ( Fig. 1d), suggesting that the level of inflammation in the tumor microenvironment did not differ significantly before treatment.…”

Section: Responses To Radiation and Pd-1 Blockadementioning

confidence: 95%

“…A gene signature that responds to interferons (ISG signature) was obtained from Liu et al 21 . Human genes were converted to mouse equivalent genes using the Ensembl database (Release 97) 57 21 were applied to the normalized expression data to summarize the expression level of the ISG signature. One-way ANOVA model and Tukey's multiple comparison test were used to compare the signature scores between all pairs of the treatment groups.…”

Section: Rna Sequencing Analysis For Differential Expressionmentioning

confidence: 99%

A single cell atlas reveals distinct immune landscapes in transplant and primary tumors that determine response or resistance to immunotherapy

Wisdom

Mowery

Qin

et al. 2020

Preprint

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Despite impressive responses in some patients, immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Nearly all preclinical immunotherapy studies utilize transplant tumor models, but cure rates of transplant tumor models treated with immunotherapy often overestimate patient responses. Here, we show that transplant tumors are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous tumors. We generated a single-cell atlas of tumor-infiltrating immune cells from transplant and primary tumors treated with radiation and immunotherapy, which reveals striking differences in their immune landscapes. Although radiotherapy remodels myeloid cell phenotypes in primary and transplant tumors, only transplant tumors are enriched for CD8+ T cells that mediate tumor clearance while mice with primary sarcomas demonstrate tumor-specific tolerance. These results identify distinct microenvironments in tumors that coevolve with the immune system, which promote tolerance that must be overcome for immune-mediated cancer cures.

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Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss

Cited by 275 publications

References 48 publications

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer

A single cell atlas reveals distinct immune landscapes in transplant and primary tumors that determine response or resistance to immunotherapy

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