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Setdb1-loss induces type-I interferons and immune clearance of melanoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE232414 | GEO | 2023/12/31

REPOSITORIES: GEO

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Setdb1-loss induces type-I interferons and immune clearance of melanoma (RNA-Seq)

Project description:Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified multiple components of the HUSH complex, including Setdb1, as hits. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner. Mechanistically, loss of Setdb1 causes de-repression of endogenous retroviruses (ERVs) in melanoma cells and triggers tumor-cell intrinsic type-I interferon signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Furthermore, spontaneous immune clearance observed in Setdb1-/- tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional anti-tumor role of ERV-specific CD8+ T-cells found in the Setdb1-/- microenvironment. Blocking the type-I interferon receptor in mice grafted with Setdb1-/- tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth comparable to Setdb1wt tumors. Together, these results indicate a critical role for Setdb1 and type-I interferons in generating an inflamed tumor microenvironment, and potentiating tumor-cell intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type-I interferon expression as potential therapeutic targets for augmenting anti-cancer immune responses.

2023-12-31 | GSE232411 | GEO

Setdb1-loss induces type-I interferons and immune clearance of melanoma (scRNA-Seq)

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Setdb1-loss induces type-I interferons and immune clearance of melanoma

Project description:Setdb1-loss induces type-I interferons and immune clearance of melanoma

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Setdb1-loss induces type-I interferons and immune clearance of melanoma (scRNA-Seq)

Project description:Setdb1-loss induces type-I interferons and immune clearance of melanoma (scRNA-Seq)

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Setdb1-loss induces type-I interferons and immune clearance of melanoma (RNA-Seq)

Project description:Setdb1-loss induces type-I interferons and immune clearance of melanoma (RNA-Seq)

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Expression analysis of melanoma harvested after GFP or SETDB1 expression

Project description:This SuperSeries is composed of the SubSeries listed below.

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HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.

Project description:BACKGROUND & AIMS:Polymorphisms in the IL28B gene have been associated with clearance of hepatitis C virus (HCV), indicating a role for type III interferons (IFNs) in HCV infection. Little is known about the function of type III IFNs in intrinsic antiviral innate immunity. METHODS:We used in vivo and in vitro models to characterize the role of the type III IFNs in HCV infection and analyzed gene expression in liver biopsy samples from HCV-infected chimpanzees and patients. Messenger RNA and protein expression were studied in HCV-infected hepatoma cell lines and primary human hepatocytes. RESULTS:HCV infection of primary human hepatocytes induced production of chemokines and type III IFNs, including interleukin (IL)-28, and led to expression of IFN-stimulated genes (ISGs). Chimpanzees infected with HCV showed rapid induction of hepatic type III IFN, associated with up-regulation of ISGs and minimal induction of type I IFNs. In liver biopsy specimens from HCV-infected patients, hepatic expression of IL-28 correlated with levels of ISGs but not of type I IFNs. HCV infection produced extensive changes with gene expression in addition to ISGs in primary human hepatocytes. The induction of type III IFNs is regulated by IFN regulatory factor 3 and nuclear factor ?B. Type III IFNs up-regulate ISGs with a different kinetic profile than type 1 IFNs and induce a distinct set of genes, which might account for their functional differences. CONCLUSIONS:HCV infection results predominantly in induction of type III IFNs in livers of humans and chimpanzees; the level of induction correlates with hepatic levels of ISGs. These findings might account for the association among IL-28, level of ISGs, and recovery from HCV infection and provide a therapeutic strategy for patients who do not respond to IFN therapy.

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Infection with Classical Swine Fever Virus Induces Expression of Type III Interferons and Activates Innate Immune Signaling.

Project description:Classical swine fever virus (CSFV) commonly infects the lymphatic tissues and immune cells of pigs and could cause a lethal disease in the animals. The process and release of cytokines like type III interferons (IFNs) is one of the important responses of the host innate immunity to viral infection. However, little information is available about type III IFN response to the CSFV infection. In this study, we investigated the expression of type III IFNs including interleukin-28B (IL-28B) and IL-29 in PK-15 cells and pigs following CSFV infection. We found that infection with CSFV was able to induce expression of IL-28B and IL-29 in PK-15 cells, although the increased levels of type III IFNs were limited. Importantly, up-regulation of IL-28B and IL-29 was further observed in CSFV infected animal tissues. The production of IL-28B and IL-29 was reduced by the inactivation of NF-?B in cells, indicating that activated NF-?B is required for efficient expression of type III IFNs induced by CSFV. Moreover, our experiments demonstrated that infection with CSFV strongly stimulated the downstream of STAT1 signaling in vitro and in vivo. In addition, several critical IFN-stimulated genes (ISGs) including IFITM3, OASL, OAS1, and ISG15 were significantly upregulated at both mRNA and protein levels in PK-15 cells and infected pigs. Together, these results reveal that CSFV can trigger host antiviral immune responses including production of type III IFNs, activation of STAT1, and induction of some critical ISGs.

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Weight loss after gastric bypass surgery in human obesity induces promoter methylation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-04-11 | E-GEOD-45747 | biostudies-arrayexpress

Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-08-30 | E-GEOD-43710 | biostudies-arrayexpress