Restoring PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
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ABSTRACT:
PROVIDER: PRJEB61737 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11274557_1.fastq.gz | Fastqsanger.gz | |||
| ERR11274557_2.fastq.gz | Fastqsanger.gz | |||
| ERR11274558_1.fastq.gz | Fastqsanger.gz | |||
| ERR11274558_2.fastq.gz | Fastqsanger.gz | |||
| ERR11274559_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint inhibitors (ICIs) are a type of cancer treatment that work by targeting molecules on immune cells that can inhibit the immune system's ability to attack cancer cells. One such checkpoint molecule is PD-1, which is found on the surface of T cells (a type of immune cell) and helps to prevent them from attacking healthy cells. When PD-1 binds to its ligand (a molecule on the surface of some cells), it sends a signal to the T cell to \\"turn off\\" and not attack the cell. This mechanism is important in preventing the immune system from attacking healthy cells, but it can also be exploited by cancer cells to avoid detection and destruction by the immune system. In this study YUMM2.1 mouse tumour cells were implanted subcutaneously. The effect of IFN-γ-pre-treatment, PARP14 inhibition and PD-1 antibody treatment are reported by RNA-seq.
2023-08-22 | E-MTAB-12872 | biostudies-arrayexpress
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-12195 | biostudies-arrayexpress
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: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:For comparison of the transcription profile between IFNγ-PD-L1all and IFNγ+PD-L1all cells, we treated KPC1199 cells with vehicle control or 10 ng/mL recombinant mouse IFNγ for 20 hours and harvested them. For comparison of PD-L1hi with PD-L1all, cells were either sorted with the top 15% PD-L1+ or total of IFNγ+PD-L1all PDAC cells, and freshly collected as soon as possible to be used for RNA preparation.
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Project description:Bulk RNA-seq analysis of IFNγ-PD-L1all, IFNγ+PD-L1all and IFNγ+PD-L1hi PDAC cells
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Project description:Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.
2024-06-22 | PXD050744 | 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: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:The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following transient PD-L1 silencing. Aerobic glycolysis, as well as signaling pathways related to inflammation, were not induced by IFNγ when PD-L1 was silenced, however, tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals.
2022-06-05 | GSE199107 | GEO