The Prostacyclin Receptor is a Nrf2-regulated Immune Checkpoint in CD8+ T cells
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ABSTRACT:
PROVIDER: PRJNA1023228 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26261366_1.fastq.gz | Fastqsanger.gz | |||
| SRR26261366_2.fastq.gz | Fastqsanger.gz | |||
| SRR26261367_1.fastq.gz | Fastqsanger.gz | |||
| SRR26261367_2.fastq.gz | Fastqsanger.gz | |||
| SRR26261368_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint inhibitor (ICI) therapies revitalize anti-cancer responses by intercepting protein-protein interactions between exhausted CD8 T (Tex) cells and cancer cells (e.g. PD-1:PD-L1). However, up to 50% of patients receiving ICIs relapse, warranting further interrogation of the underpinnings of Tex. We conducted RNA-seq meta-analysis of Tex versus effector (Teff) mouse CD8 T cells, and highlighted NRF2 transcriptional targets as the most upregulated gene set in Tex cells. LCMV or cancer inoculation of mice bearing NRF2 hyperactive—or Keap1-/- (NRF2 negative regulator)—T cells demonstrated that NRF2 drives Tex; evidenced by increased co-inhibitory marker (PD-1/TIM-3) expression and reduced cytokine (IFN-g/Granzyme-B) production. RNA-seq of Keap1-/- highlight Ptgir—which encodes the prostacyclin lipid receptor— as the most upregulated gene versus WT T cells. Accordingly, PTGIR knockout in NRF2-hyperactive/ Tex cells decreased PD-1/TIM-3 expression, increased cytokine production, and attenuated tumor growth. Our data underscore PTGIR as a NRF2-regulated Tex driver and illuminate an unconventional immune checkpoint class potentially based on protein-lipid interactions
2025-04-25 | PXD052688 | Pride
Project description:Understanding how circulating metabolites enforce pathways in dysfunctional immune cells may illuminate modes of intervention directed at reviving immune function. The NRF2 pathway is the most widely documented cytoprotective axis in land-dwelling eukaryotes. However, the role of this pathway in CD8+ T cells—which seek and destroy tumors and pathogen infected cells—has yet to be elucidated. Our lab has conducted a RNAseq meta-analysis of CD8+ T cells upon tumor, viral and bacterial inoculation. Curiously, the NRF2 pathway was robustly upregulated in dysfunctional CD8+T cells. To further investigate the role of NRF2 in these contexts we developed a mouse model whereby the NRF2 axis is permanently hyperactivated in CD8+ T cells, hereafter referred to as NRF2Hi. Our in vivo data demonstrate that NRF2Hi CD8+ T cells offer little overall cytoprotection and poorly control tumors and pathogens versus wildtype (WT) control CD8+ T cells. To understand why upregulation of the NRF2 axis could be unfavorable to CD8+ T cell function we conducted RNAseq on NRF2Hi versus WT cells upon viral infection of mice. We found that NRF2Hi cells massively upregulate the prostacyclin receptor (PTGIR), which binds to prostacyclin—a circulating metabolite of arachidonic acid that has only been investigated in vasodilation and is seemingly benign to CD8+ T cells. To decipher the role of PTGIR in CD8+ T cells, we silenced its expression and observed a revival of CD8+ T cell function, significantly reducing tumor and pathogen burden. Collectively, our data illuminate a NRF2-regulated immune checkpoint, PTGIR. Interventions that suppress the interaction between PTGIR and prostacyclin may serve therapeutic benefit in clinical contexts such as cancer and chronic pathogen infections.
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Project description:The progressive decline of CD8 T cell effector function, also known as T cell “exhaustion” (Tex), is a major contributor to immune evasion in cancer, yet the molecular mechanisms that promote this decline remain poorly understood. Here, we identify the prostaglandin I2 receptor (PTGIR) as a cell-intrinsic driver of CD8 T cell dysfunction. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, in terminally exhausted (Tex-term) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+/TIM-3+) CD8 Tex cells in response to chronic infection or tumor challenge. NRF2 promotes the increased expression of PTGIR, a receptor for the circulating eicosanoid prostacyclin, in CD8 T cells. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient CD8 T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-gamma and granzyme production) to chronic infection and cancer. Mechanistically, PTGIR signaling blunts both bioenergetic metabolism and effector cytokine production in CD8 T cells and promotes a Tex cell signature marked by high expression of interferon-stimulated genes (ISGs). Together, these results identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.
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Project description:Cellular oxidative and electrophilic stress triggers a protective response in mammals regulated by NRF2 (nuclear factor (erythroid-derived) 2-like; NFE2L2) binding to DNA-regulatory sequences near stress responsive genes. Studies using Nrf2-deficient mice suggest that hundreds of genes may be regulated by NRF2. To identify human NRF2-regulated genes, we conducted ChIP-sequencing experiments in lymphoid cells treated with the dietary isothiocyanate, sulforaphane (SFN) and carried out follow-up biological experiments on candidates. We found 242 high-confidence, NRF2-bound genomic regions and 96% of these regions contained NRF2-regulatory sequence motifs. The majority of binding sites were near potential novel members of the NRF2 pathway. Validation of selected candidate genes using parallel ChIP techniques and in NRF2-silenced cell lines indicated that the expression of about two thirds of the candidates are likely to be directly NRF2-dependent including retinoid X receptor alpha (RXRA). NRF2 regulation of RXRAhas implications for response to retinoid treatments and adipogenesis. In mouse 3T3-L1 cells SFN treatment affected Rxra expression early in adipogenesis and knockdown of Nrf2 delayed Rxra expression, both leading to impaired adipogenesis. ChIP-Seq analysis of NRF2 binding sites in human lymphoblastoid cells treated with sulforaphane or vehicle
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Project description:CAFs, ascTAMs and M1- and TAM-like-MDMs were treated with 1 μM of the Prostacyclin analoga MRE and DMSO (as solvent control). The aim of this experiment is to see which effect MRE (Prostacyclinanaloga) has on RNA expression (activation of signaling pathways). Background: Prostacyclin receptor expression is elevated in TAMs. Prostacyclinsynthase expression was detected mainly in CAFs. (
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