MRNA sequencing of lung cancer cell lines before and after stimulation with IFNγ
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE186169 | GEO | 2023/03/16
REPOSITORIES: GEO
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Project description:The anti-tumor effects of IFNγ are well-known as IFNγ binding to tumor cells increases antigen presentation and can cause cytostatic growth defects. Indeed, the inability of tumors to respond to IFNγ often renders tumors resistant to checkpoint blockade and other immunotherapies reliant on direct T cell cytotoxicity. We performed single-cell RNA-sequencing during virus therapy to get insight into the immune microenvironment of the tumor during treatment.
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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: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: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.
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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
Project description:The anti-tumor effects of IFNγ are well-known as IFNγ binding to tumor cells increases antigen presentation and can cause cytostatic growth defects. Indeed, the inability of tumors to respond to IFNγ often renders tumors resistant to checkpoint blockade and other immunotherapies reliant on direct T cell cytotoxicity. We demonstrate through RNA-sequencing that IFNgR1-/- and STAT1-/- tumors are defective in their response to IFNγ compared to wild-type tumors.
2023-02-06 | GSE212829 | GEO
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.
2023-08-08 | E-MTAB-12194 | biostudies-arrayexpress
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:Purpose: The goal of this study is to compare transcriptome profiles of IFNγ producing (Thy1.1+) and IFNγ non-producing (Thy1.1-) CD4 T cells during chronic intestinal inflammation using RNA sequencing. Methods: Total mRNA was isolated from FACS sorted CD44+Thy1.1+ and CD44+Thy1.1-CD4 T cells and sequenced in duplicate using Illumina HiSeq 2500 (2x100 base pair, paired-end reads). The sequence reads were aligned using mouse GRCm38.75 reference genome. DESeq2 software was used for differential expression analysis. Results: Differential expression analysis with DESeq2 algorithm revealed that a total of 942 and 1091 genes were significantly increased in the IFNγ+ and IFNγ- effector CD4 T cells, respectively (adjusted p value <0.05). We also performed gene set enrichment analysis (GSEA) by pre-ranking RNA sequencing data according to an adjusted p-value and the sign of differential expression. GSEA regults suggested that IFNγ+ CD4 T cells had terminally differentiated phenotype, while IFNγ- CD4 T cells had transcriptional profile associated with self-renewal and stemness. Conclusions: Our study suggests that effector CD4 T cells exist in a spectrum of differentiation status during chronic intestinal inflammation, which impacts pathogenicity of CD4 T cells.
2018-05-12 | GSE114346 | 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