Enhancing tumor response to adoptive T cell therapy by targeting PHD2/3 in CD8 T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1130998 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29931366_1.fastq.gz | Fastqsanger.gz | |||
| SRR29931366_2.fastq.gz | Fastqsanger.gz | |||
| SRR29931367_1.fastq.gz | Fastqsanger.gz | |||
| SRR29931367_2.fastq.gz | Fastqsanger.gz | |||
| SRR29931368_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 36 |
Similar Datasets
Project description:In our study, we utilized cutting-edge CrisPR-Cas9 technology to evaluate the effects of deleting prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3, which stabilizes HIF-1 signaling, in CD8 T cells that have already undergone differentiation and activation, mirroring the conditions encountered in clinical settings. Our study revealed a significant boost in T-cell activation and effector functions after PHD2/3 deletion, and conclusively established its dependence on HIF-1. This improvement in CD8 T cell performance translated into a remarkable enhancement in the response to adoptive T cell therapy, across various tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. Furthermore, our data provide compelling evidence that the increased effector functions observed in PHD-deficient (KO) CD8 T cells are intricately linked to an increased glycolytic flux. These findings hold significant promise for advancing CD8 T -cell based therapies and overcoming the immune suppression barriers within challenging tumor microenvironments.
2024-07-09 | GSE271367 | GEO
Project description:LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness
| PRJNA1138703 | ENA
Project description:The PHD/HIF pathway has been implicated in a wide range of immune and inflammatory processes, including in the oxygen‐deprived tumor microenvironment. To examine the effect of HIF stabilization in anti‐tumor immunity, we deleted Phd2 selectively in T lymphocytes using the cre/lox system. We show that the deletion of PHD2 in lymphocytes resulted in enhanced regression of EG7‐OVA tumors, in a HIF‐1adependent manner. The enhanced control of neoplastic growth correlated with increased poly‐functionality of CD8+ tumor‐infiltrating lymphocytes, i.e. enhanced expression of IFN‐g, TNF‐a and granzyme B. Phenotypic and transcriptomic analyses point to a key role of glycolysis in sustaining CTL activity in the tumor bed and identifies the PHD2/HIF‐1 pathway as potential target for intervention.
2022-12-01 | GSE216536 | GEO
Project description:Effector CD8+ T cell (TE) proliferation and cytokine production depends on enhanced glucose metabolism. However, circulating T cells continuously adapt to glucose fluctuations caused by diet and inter-organ metabolite exchange. Here we show that transient glucose restriction (TGR) in activated CD8+ TE metabolically primes effector functions and enhances tumour clearance in mice. Tumor-specific TGR CD8+ TE co-cultured with tumor spheroids in replete conditions display enhanced effector molecule expression, and adoptive transfer of these cells in a murine lymphoma model leads to greater numbers of immunologically functional circulating donor cells and complete tumor clearance. Mechanistically, TGR TE undergo metabolic remodelling that upon glucose re-exposure supports enhanced glucose uptake, increased carbon allocation to the pentose phosphate pathway (PPP), and a cellular redox shift toward a more reduced state, all indicators of a more anabolic program to support their enhanced functionality. Thus, metabolic conditioning could be utilized to promote efficiency of T cell products for adoptive cellular therapy.
2020-08-03 | GSE152018 | GEO
Project description:The lysine-specific histonedemethylase1A(LSD1) has been described to play a role in antitumor immunity; however, the role of LSD1 in shaping CD8+ T cell (CTL) differentiation and function is not understood. Here, we showed that pharmacological inhibition of LSD1 (LSD1i) in CTL elicited phenotypic and functional alterations of the CTL that led to robust antitumor immunity in the context of adoptive T cell therapy (ACT). In addition, the combination of anti-PDL1 therapy with LSD1i-based ACT resulted in a complete tumor eradication and long-lasting tumor-free survival. This study demonstrated that LSD1i together with anti-PDL1 therapy complement each other’s deficiencies and produce a better tumor response in a melanoma model, in which both immune and epigenetic therapy alone have shown limited efficacy. Collectively, these results set the translational potential of modulating LSD1 to improve antitumoral responses generated by ACT and anti-PDL1 therapy, which provide a strong rationale for a combination trial of LSD1i and immunotherapy.
2024-07-23 | GSE272770 | GEO
Project description:The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.
| 63320 | ecrin-mdr-crc
Project description:PHD2 constrains the anti-tumor CD8+ T cell activity
| PRJNA894180 | ENA
Project description:Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy
| PRJNA638107 | ENA
Project description:To identify novel regulator of EGLN1/PHD2, we performed label-free quantitative interactome analysis. Stable Hela cell lines expressing Flag-tagged PHD2 and control vector were generated. Immunoprecipitation and mass spectrometry analysis were performed to identify novel interactors of PHD2 followed by validation and functional analysis.
2021-09-08 | PXD014757 | Pride
Project description:IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naïve CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of eomesodermin and maturation of naïve CD8+ T cells into granzyme B and CD44 expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2, surprisingly, impaired the subsequent anti-tumor function of transferred cells. Gene expression studies revealed a distinct IL-21-program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced anti-tumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies. Two-condition experiment: Cytokine-exposed t-cells subsequentially restimulated without cytokine vs. control t-cells without cytokine subsquentially restimulated without cytokine. 3 independent experiments - 1 with experimental RNA labeled with Cy5, control with Cy3, and 2 with dyes-swapped Keywords: Cytokine exposure comparison Comparitive analysis of cytokine effects on lymphocyte gene expression. GSM265712.gpr (S89_1_IL2_0.gpr): Cy3 - control, Cy5 - experimental GSM265713.gpr (S90_1_IL15_0.gpr): Cy3 - control, Cy5 - experimental GSM265714.gpr (S91_1_IL21_0.gpr): Cy3 - control, Cy5 - experimental GSM265715.gpr (S27_2_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265716.gpr (S29_2_0_IL15.gpr): Cy3 - experimental, Cy5 - control GSM265717.gpr (S30_2_0_IL21.gpr): Cy3 - experimental, Cy5 - control GSM265718.gpr (S31_3_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265719.gpr (S33_3_0_IL15.gpr): Cy3 - experimental, Cy5 - control
2010-05-26 | E-GEOD-10403 | biostudies-arrayexpress