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Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (IFNg treatment and GRASLND KD).

ABSTRACT: Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (IFNg treatment and GRASLND KD).

PROVIDER: PRJNA1139801 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29979757_1.fastq.gz	Fastqsanger.gz
	SRR29979757_2.fastq.gz	Fastqsanger.gz
	SRR29979758_1.fastq.gz	Fastqsanger.gz
	SRR29979758_2.fastq.gz	Fastqsanger.gz
	SRR29979759_1.fastq.gz	Fastqsanger.gz

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Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (IFNg treatment and GRASLND KD).

Project description:Melanoma is a highly malignant tumor, that stands as the most lethal form of skin cancer and is characterized by notable phenotypic plasticity and intratumoral heterogeneity. Melanoma plasticity is involved in tumor growth, metastasis and therapy resistance. Long non-coding RNAs (lncRNAs) could influence plasticity due to their regulatory function. However, their role and mode of action are poorly studied. Here, we show a relevance of lncRNA GRASLND in melanoma phenotypic switch, IFNγ signaling and immunogenicity. GRASLND knockdown revealed switching towards a dedifferentiated, slow-proliferating and highly-invasive cell state. Interestingly, GRASLND is overexpressed in differentiated melanomas and associated with poor prognosis. Accordingly, we found GRASLND expressed in immunological “cold” tumors and it negatively correlates with gene signatures of immune response activation. In line, silencing of GRASLND under IFNγ enhanced the expression of IFNγ-stimulated genes, including HLA-I antigen presentation, demonstrating suppressive activity of GRASLND on IFNγ signaling. Based on our findings, we hypothesize an adaptive resistance mechanism of melanoma cells evading the immune system via inhibition of IFNγ signaling by GRASLND overexpression and highlight its value as a negative prognostic factor for melanoma.

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Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (GRASLND KD).

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Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (GRASLND KD).

Project description:Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (GRASLND KD).

| PRJNA1139800 | ENA

Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. IFNG Study.

Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.

2023-08-22 | E-MTAB-12196 | biostudies-arrayexpress

IFNg+ vs IFNg- Treg

Project description:Gene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood Ex vivo sorted Tregs (CD25highCD127neg) were stimulated for 4 hours and IFNg-secreting cells were detected by a IFNg-capture kit. The samples were resorted based on IFNg expression.

2016-07-01 | E-GEOD-71274 | biostudies-arrayexpress

UBIQUITIN LIGASE STUB1 DESTABILIZES IFNγ-RECEPTOR COMPLEX TO SUPPRESS TUMOR IFNγ SIGNALING

Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.

2022-03-07 | PXD030580 | Pride

IFNg+ vs IFNg- Treg

Project description:Gene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood

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Mouse trophoblast cells have attenuated responses to TNFα and IFNγ that allow them to avoid synergic cytotoxicity of the two cytokines

Project description:TNFα and IFNg are two inflammatory cytokines that play critical roles in immune responses, but they can also negatively affect cell proliferation and viability. In particular, the combination of the two cytokines (TNFα/IFNγ) synergistically causes death in many cell types. We recently demonstrated that, mouse embryonic stem cells (ESCs) isolated from the inner cell mass of the blastocyst stage embryo, do not respond to TNFα and IFNg, thereby avoiding TNFα/IFNγ cytotoxicity. This study expanded our investigation to mouse trophoblast stem cells (TSCs) and differentiated trophoblasts (TSC-TBs), the major cellular constituents in trophectoderm of the blastocyst. We report here that TNFα or IFNγ alone has limited negative effect on the viability of mouse fibroblasts, but TNFα/IFNγ effectively kill these cells. However, TSCs and TSC-TBs are markedly resistant to the cytotoxicity of TNFα/IFNγ. With molecular and cellular approaches and transcriptomic analysis, we demonstrated that TSCs and TSC-TBs have attenuated responses to TNFα and IFNγ and the underlying molecular mechanisms that allow these cells to avoid the synergistic cytotoxicity of TNFα/IFNγ. Together with our previous findings in ESCs, we propose that the attenuated responses of TSCs, TSC-TBs, and ESCs to TNFα and IFNγ may serve as a protective mechanism that limits cytokine cytotoxicity in the blastocyst.

2023-11-10 | GSE224755 | GEO

Chromatin accessibility in naive and primed HeLa cells upon IFNγ treatment

Project description:chromatin accessibility (ATAC-seq) experiment. HeLa cells were primed with IFNγ for 24 hours, followed by IFNγ washout. After 48h, naïve and primed cells were induced by IFNγ for 1h and 3h. Cells were harvested at indicated time points and processed for ATAC-seq.

2023-05-06 | E-MTAB-12624 | biostudies-arrayexpress

STUB1 dampens IFNγ response in tumors by destabilizing the IFNγ receptor complex

Project description:Despite its success, immune checkpoint blockade (ICB) cannot induce durable responses in most patients. This is partially attributed to reduced sensitivity to interferon gamma (IFNγ). Thus, elevating tumor IFNγ-receptor 1 (IFNγ-R1) expression to enhance IFNγ-mediated cytotoxicity is of clinical interest. Here, we demonstrate higher IFNγ-R1 expression to sensitize tumors to IFNγ-mediated killing. To unveil the largely undefined mechanisms of IFNγ-R1 expression, we performed a genome-wide CRISPR/Cas9 knockout screen for suppressors of IFNγ-R1 tumor cell surface abundance. We uncovered STUB1 as key mediator for proteasomally degrading IFNγ-R1/JAK1 complex. Conversely, STUB1 inactivation in tumor cells amplified IFNγ signaling and sensitized to cytotoxic T cells, but permitted IFNγ-induced PD-L1 expression. Rationally combining STUB1 inactivation with anti-PD-1 treatment effectively eliminated tumors in vivo. Clinically corroborating this is a STUB1 transcriptomic signature that associates with response to anti-PD-1 treatment in two patient cohorts. Thus, uncovering STUB1 as a pivotal regulator of IFNγ signaling and a synergistic target for anti-PD-1 treatment.

2022-02-24 | GSE154040 | GEO

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