IFNγ-dependent remodelling of the myeloid immune landscape underlies control of IFNγ-insensitive tumors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE260972 | GEO | 2024/03/09
REPOSITORIES: GEO
Similar Datasets
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
Project description:Transcriptome analysis of IFNγ-insensitive DCs IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population. We analyzed saliva from 3 WT DC samples and 3 IFNγR2 KO DC samples isolated from unmanipulated mice. In addition, we analyzed saliva from 3 WT DC samples and 3 IFNγR2 KO DC samples isolated from mixed BM chimeras (WT + IFNgR2KO) day 8 T. gondii infected.
2015-01-01 | E-GEOD-64594 | biostudies-arrayexpress
Project description:STUB1 dampens IFNγ response in tumors by destabilizing the IFNγ receptor complex
| PRJNA644914 | ENA
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
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
Project description:Transcriptome analysis of IFNγ-insensitive DCs IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.
2015-01-01 | GSE64594 | GEO
Project description:STAT1 and IRF1 transcription factor enrichment by CUT&RUN. HeLa cells were primed with IFNγ for 24 hours, followed with 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 CUT&RUN
2023-05-06 | E-MTAB-12625 | biostudies-arrayexpress
Project description:While it is clear that T cell derived IFNγ has to act on tumor stroma cells for rejection of solid tumors, it is not clear which tumor stroma cells are targets. We studied how IFNγ affects gene expression in tumor blood vessels in vivo. To study the effect on endothelial cells, we either used a model of ectopic IFNγ (MCA313 tumors) or IFNγ-GFP fusion protein (J558L tumors) expression in tumors, or we used T cell derived IFNγ in large vascularized 16.113 tumours. Tumors were grown in mice that were expressing the IFNγ receptor ubiquitously (J558L tumors + IFNγ-GFP treatment and 16.113 tumors + T cell treatment) or in some experiments the IFNγ-receptor was expressed exclusively in endothelial cells (MCA313 tumor + IFNγ treatment). We compared RNA expression profiles from mouse endothelial cells exposed to IFNγ (IFNγ-GFP) or not exposed to IFNγ (IFNγ-GFP). Endothlial cells were drived from tumors (or in one experimantal situation -J558L- as a control also from kidney)
2017-05-04 | GSE94504 | GEO
Project description:Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for spontaneous rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. Microarray data showed a 3-fold increase in interferon (IFN)-γ and a 2.7-fold increase in Fas ligand (FasL). There was a robust increase in transcripts (127 of 408 surveyed) from interferon (IFN)-stimulated genes and a marked decrease (in 40 of 192 surveyed) in the expression of cell-cycle-associated genes. Non-microarray data confirmed that IFNγ, FasL and CD8+ T cells but not perforin or TNFα were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthsis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1-/- mice and Fas-defective lpr mice failed to eliminate ocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras showed that immune cell expression of IFNγR1 and Fas was critical and that SPLNX increased the frequency of activated macrophages within ocular tumors in an IFNγ- and Fas/FasL-dependent manner. Rejection of intraocular tumors was associated with increased ocular mRNA expression of several inflammatory genes including FasL, NOS2, CXCL2 and T-bet. Our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral macrophage by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis. The immunosuppressive mechanisms which maintain ocular IP likely interfere with the interaction between CD8+ T cells and macrophage to limit immunosurveillance of intraocular tumors. C57BL/6 mice that were splenectomized (Tumor_splnx) or were not surgically manipulated (Tumor_intact) were challenged with 10^4 luciferase-expressing E.G7-OVA cells injected into the anterior chamber of the eye. Fifteen days later, the animals were euthanized and tumor-bearing eyes were removed.
2014-07-01 | E-GEOD-57101 | biostudies-arrayexpress
Project description:Affymetrix arrays measuring gene expression in 3 Drosophila Insensitive mutant embryos and 3 Drosophila wt mutant embryos 6 samples, 3 replicates of Insensitive mutants and 3 replicates of wt
2013-04-04 | E-GEOD-44177 | biostudies-arrayexpress