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ICOS limits memory-like properties and function of exhausted PD-1+ CD8 T cells [ATAC-seq]

ABSTRACT: During persistent antigen stimulation, PD-1+CD8 T cells are maintained by progenitor exhausted PD-1+TCF-1+CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1+CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory features of Tpex. ICOS-deficient Tex displayed enhanced survival and improved cytokine production. In chronically-infected mice, ICOS-Ligand blockade expanded effector-like Tex, reduced viral load and potentiated anti-PD-L1 therapy. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1+CD8 T cells and sensitized tumors to PD-1 targeted therapy. Overall, we show that sustained ICOS costimulation limits CD8 T cell responses during chronic antigen exposure.

ORGANISM(S): Mus musculus

PROVIDER: GSE288889 | GEO | 2025/07/07

REPOSITORIES: GEO

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ICOS limits memory-like properties and function of exhausted PD-1+ CD8 T cells [RNA-seq]

Project description:During persistent antigen stimulation, PD-1+CD8 T cells are maintained by progenitor exhausted PD-1+TCF-1+CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1+CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory features of Tpex. In mice with established chronic infection, ICOS-Ligand blockade resulted in expansion of effector-like Tex and reduction in viral load. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1+CD8 T cells and delayed tumor growth. Overall, we show that ICOS constrains CD8 T cell responses during chronic antigen exposure.

2025-07-07 | GSE270420 | GEO

Single cell analysis of splenic control and ICOS deficient P14 cells from LCMV chronically infected mice

Project description:During persistent antigen stimulation, PD-1+CD8 T cells are maintained by progenitor exhausted PD-1+TCF-1+CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible T-cell Costimulator (ICOS), but the role of ICOS for PD-1+CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory features of Tpex. In mice with established chronic infection, ICOS-Ligand blockade resulted in expansion of effector-like Tex and reduction in viral load. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1+CD8 T cells and delayed tumor growth. Overall, we show that ICOS constrains CD8 T cell responses during chronic antigen exposure.

2025-07-07 | GSE270606 | GEO

Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite.

Project description:The gut microbiome serves as a crucial mediator for improving the efficacy of immune checkpoint blockade (ICB) therapy. Here, we show that oral supplementation with prebiotics (mannose) retarded tumor growth in immunocompetent mice in a gut microbiota dependent manner, correlating with the enrichment of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME) characterized by an increase percentage of effector and memory CD8+T cells, accompanied by a prominent immunoreactivegeneexpressionsignature. Most importantly, mannose modulates the stemness program of CD8+T cells and facilitates the generation of progenitor exhausted CD8+T cells (Tpex). Mechanistically, mannose increases gut microbial production of the short-chain fatty acids (SCFA) propionate and butyrate. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Mannose synergized with PD-1 blockade in tumor regression and augmented intratumoral Tpex differentiation into intermediate exhausted CD8+T cells (Tex-int) and terminally exhausted CD8+T cells (Tex-term). Moreover, we identified a mannose-therapy related gene signature associated with favorable responses to ICB in pan-cancer. Overall, our findings support the rationale for combining dietary supplementation of mannose with anti-PD-1 immunotherapy in ovarian cancer, and its clinical translation.

2025-03-17 | GSE271477 | GEO

Contrasting functions of CD73 and adenosine in CD8+ T cell exhaustion

Project description:T cell exhaustion is a state of functional decline in T cells, driven by chronic antigen exposure and inhibitory signals within the tumor microenvironment. Exhausted CD8+ T cells (Tex) derive from precursor exhausted T cells (Tpex), a self-renewing population responsible for the proliferative burst observed in anti-PD-1 therapies. Exhausted cells are exposed to adenosine in the tumor, yet the role of the CD73/adenosine axis and Tpex/Tex differentiation remains unclear. Using an in vitro model for CD8+ T cell exhaustion, we found that CD73 expression increased during Tpex formation and that its expression is negatively correlated with Tex generation. CD73-deficient (CD73KO) CD8⁺ T cells showed impaired activation and reduced progression to Tex. Moreover, we demonstrated that CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR) and the differentiation into IFNγ/TNFα-producing Tex cells. RNAseq analysis of exhausted CD73KO CD8+ T cells showed a more stem-like transcriptomic profile and enrichment in genes associated with the immune response than their WT counterpart. In vivo, co-transfer of naïve CD73 KO and WT tumor antigen-specific CD8⁺ T cells into tumor-bearing mice showed increased Tpex frequency and numbers among CD73KO cells in tumors. Conversely, in vitro exhaustion in the presence of A2AR agonists decreased Tex frequency and activation/exhaustion markers, while increasing CD73 and CD62L, markers associated with stemness. Supporting this, A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation. Altogether, our data suggest CD73 promotes Tpex-to-Tex differentiation, whereas adenosine-A2AR signaling supports Tpex maintenance in the tumor microenvironment.

2025-05-30 | GSE298159 | GEO

Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite [CD8]

Project description:The gut microbiome plays a critical role in enhancing the effectiveness of immune checkpoint blockade (ICB) therapy. Here, we demonstrate that oral supplementation with the prebiotics mannose slows tumor growth in immunocompetent mice in a manner dependent on the gut microbiota. This effect is associated with an increase in the abundance of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME), characterized by a higher percentage of effector and memory CD8+ T cells, along with a notable immunoreactive gene expression signature. Crucially, mannose modulates the stemness program of CD8+ T cells and promotes the generation of progenitor exhausted CD8+ T cells (Tpex). Mechanistically, mannose enhances the production of the short-chain fatty acids (SCFA) propionate and butyrate by the gut microbiota. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Furthermore, mannose works synergistically with PD-1 blockade, resulting in tumor regression and enhanced differentiation of intratumoral Tpex into intermediate exhausted CD8+ T cells (Tex-int) and terminally exhausted CD8+ T cells (Tex-term). We also identified a gene signature related to mannose therapy that correlates with favorable responses to ICB across various cancers. Overall, our findings support the combination of mannose dietary supplementation with anti-PD-1 immunotherapy in treating ovarian cancer and suggest its potential for clinical application.

2025-03-17 | GSE285964 | GEO

Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite

2025-03-17 | GSE285806 | GEO

Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite [Peritoneum]

2025-03-17 | GSE285965 | GEO

Strength of CD28 costimulation directs self-renewal or differentiation of TCF-1+ PD-1+ CD8 T cells through metabolic regulation

Project description:During persistent antigen stimulation, such as in chronic infections and cancer, T cells differentiate into a hypofunctional exhausted state to survive. Exhausted PD-1+ CD8 T cell responses are sustained by TCF-1+ precursors (Tpex) that self-renew or differentiate into exhausted T cells (Tex) that retain some effector function. Tpex have high expression of the costimulatory molecule CD28 and are the cells that respond to PD-1 targeted immunotherapy. Here, we demonstrate that abrogation of CD28 signaling impairs maintenance of anti-viral T cell responses during chronic infection. Low-level CD28 signaling was required to preserve mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation. Our findings show that CD28 signaling is essential for long-term maintenance of antigen-specific T cells during chronic stimulation, and suggest that the activation status of antigen presenting cells determines Tpex differentiation into more functional effector-like Tex cells.

2023-07-01 | GSE200506 | GEO

Expression data from CD8 T cells from LCMV-Clone13 infected mice after two weeks of control or anti-PD-L1 treatment

Project description:Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.

2016-10-31 | GSE86796 | GEO

The Prostacyclin Receptor is a NRF2-regulated Immune Checkpoint in CD8 T cells

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

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