Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of Medium-Chain Fatty Acid Receptor GPR84 Enhances Metabolism, Cytotoxicity and Anti-Tumor Function of CD8 T cells

ABSTRACT: GPR84 is a medium-chain free fatty acid receptor predominately expressed on myeloid cells. Previous studies identified GPR84 as an enhancer of pro-inflammatory myeloid cell response and a regulator of metabolic homeostasis. However, the role of GPR84 on T cell function and metabolism remains wholly unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro, and examined its effect on anti-tumor function in adoptive cellular therapy models. Inhibition of GPR84 with the antagonist GLPG1205 promoted CD8+ T cell differentiation, proliferation, cytokine production, and cytotoxicity. This effect was confirmed using CRISPR-Cas9 GPR84 deleted CD8+ T cells. In contrast, treatment with the GPR84 agonist DL175 inhibited proliferation, cytokine production and cytotoxicity. These functional changes were paralleled by changes in metabolic activity. GPR84 antagonist GLPG1205 increased glucose uptake, glycolysis, oxidative phosphorylation (OXPHOS) and ATP production, which enhanced the energetic fitness of CD8+ T cells. Furthermore, stimulation of antigen-specific CD8+ T cells with GPR84 antagonist in vitro, or deletion of GPR84 in antigen specific T cells before adoptive cellular therapy resulted in a significantly enhanced anti-tumor effect in vivo. This study is the first demonstration that GPR84 modulation in T cells can enable more effectively killing of tumor cells and reduce tumor growth, and opens a novel approach to significantly enhance the efficacy of adoptive cellular therapies including CAR-T, TIL or CAR-NK cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE241488 | GEO | 2025/12/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Nanoinducers-mediated Mitochondria-Selective Degradation Enhance T Cell Immunotherapy Against Multiple Cancers

Project description:<p>Cancer immunotherapy utilizing cytotoxic T lymphocytes (CTLs) has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondria content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumor therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T-cell therapy, CAR T-cell therapy and tumor vaccine-based immunotherapy.</p>

2025-03-13 | MTBLS12284 | MetaboLights

Siglec-G suppresses CD8+ T cells responses through metabolic rewiring and can be targeted to enhance tumor immunotherapy

Project description:CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, their effector function can be severely impaired due to inhibitory receptors such as PD-1 and Tim-3. Here we identify Siglec-G as a novel coinhibitory receptor that limits CD8+ T cell function. Siglec-G is highly expressed on tumor-inﬁltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. Mechanistically, sialic acids on tumor cells trigger Siglec-G-SHP2 axis in CD8+ T cells, and impairs metabolic reprogramming from OXPHOS to glycolysis, which dampens CTL activation, expansion and cytotoxicity. These findings deﬁne a critical role for Siglec-G in inhibiting CD8+ T cell responses, which strongly suggests its therapeutic effect in adoptive T cell therapy and tumor immunotherapy.

2024-12-18 | GSE272544 | GEO

The lectin Siglec-G functions as an inhibitory receptor in CD8+ T cell and can be targeted to enhance therapeutic antitumor immunity.

Project description:CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, the effector function of CD8+ T cells may be severely influenced due to inhibitory receptors. Here we identify Siglec-G as a coinhibitory receptor that plays a critical role in limiting the function of CD8+ T cells. Siglec-G is highly expressed on both human and murine tumor-inﬁltrating T cells, and SiglecG+ T cells enriched in the exhausted T cell subset. CD24-Siglec-G-SHP2 axis negatively regulates PI3K-AKT signaling and impairs metabolic reprogramming in CD8+ T cells and thereby dampens their activation, expansion and cytotoxicity. Genetic ablation of Siglec-G can enhance the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. These results deﬁne a key role for Siglec-G in inhibiting CD8+ T cell-dependent responses, which strongly suggested its therapeutic effect in adoptive T cell therapy and tumor immunotherapy.

2024-12-18 | GSE255336 | GEO

Clonal kinetics and single cell transcriptional profiling of adoptively transferred CD19-specific CD8+ CAR-T cells in adults with B cell malignancies

Project description:Lymphodepletion chemotherapy followed by infusion of T cells modified to express a CD19-targeting chimeric antigen receptor (CAR) has produced remarkable anti-tumor responses in patients with B cell malignancies. However, little is known about the clonal composition and transcriptional heterogeneity of CAR-T cells in the infusion products (IP) and clonal kinetics after adoptive transfer. We performed single-cell RNA sequencing (scRNA-seq) on CD8+ CAR-T cells isolated from the IP and the blood of patients treated on a phase 1 clinical trial (NCT01865617) with lymphodepletion chemotherapy and a defined formulation of CD4+ and CD8+ CD19-specific CAR-T cells. Infused CD8+ CAR-T cells displayed transcriptional heterogeneity which declined after adoptive transfer, coincident with early expression of genes associated with activation. We identified four transcriptionally distinct CAR-T cell subsets in the IP and found that these subsets differed in their contributions to the CAR-T cell population detected in blood after infusion. Better understanding of the kinetics of clonal expansion of CAR-T cells after adoptive transfer may provide insight into strategies to improve CAR-T cell immunotherapy.

2019-11-22 | GSE125881 | GEO

Transcriptomic changes in F9 tumors after EDA-CART cell therapy

Project description:Transcriptomic analysis of tumor tissues isolated from animals bearing F9 teratocarcinoma. 129Sv mice were challenged with F9 tumor cells and, when tumors were palpable, mice were treated with EDA CAR-T s (a mixture of 1×107 CD4+ and 2×106 CD8+ CAR-T cells)or left untreated. 14 days after adoptive transfer, RNA was isolated from tumors for their transcriptomic analysis.

2022-08-10 | GSE204887 | GEO

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [CULTURED_NCT07]

Project description:Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22 (IL-22), IL-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.

2022-07-03 | GSE207314 | GEO

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [IN_VIVO_AW3]

2022-07-03 | GSE207312 | GEO

Releasing the mitochondrial respiration brake MCJ/DnaJC15 enhances CD8 CAR-T cell therapy efficacy

Project description:Metabolism of chimeric antigen receptor (CAR) T cells is emerging as an important area to improve CAR-T cell therapy in cancer treatment. Mitochondrial respiration is essential for survival and function of CAR-T cells, but developing strategies to specifically enhance mitochondrial respiration has been challenging. Here we identify MCJ/DnaJC15, an endogenous negative regulator of mitochondrial Complex I, as a metabolic target to enhance mitochondrial respiration in CD8 CAR-T cells. Loss of MCJ in CD8 CAR-T cells increases their in vitro and in vivo efficacy against mouse B cell leukemias. MCJ deficiency in TCR- specific CD8 cells also increases their efficacy against solid tumors in vivo. Furthermore, we reveal that human CD8 cells express MCJ and that silencing MCJ expression increases mitochondrial metabolism and anti-tumor activity of human CAR-T cells. Thus, we demonstrate the unique therapeutic potential of targeting MCJ to enhance the metabolism and efficacy of adoptive T cell therapies.

2024-05-02 | GSE263259 | GEO

BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion [RNA-Seq]

Project description:Chimeric antigen receptor (CAR) T-cells have not induced meaningful clinical responses in solid tumor indications. Loss of T-cell stemness, poor expansion capacity and exhaustion during prolonged tumor antigen exposure are major causes of CAR T-cell therapeutic resistance. scRNA-sequencing analysis of CAR T-cells from a first-in-human trial in metastatic prostate cancer identified two distinct and independently validated cell states associated with antitumor potency or lack of efficacy. Low levels of the PRDM1 gene encoding the BLIMP1 transcription factor defined highly potent TCF7+CD8+ CAR T-cells, while enrichment of TIM3+CD8+ T-cells with elevated PRDM1 expression predicted poor outcome. PRDM1 single knockout promoted TCF7-dependent CAR T-cell stemness and proliferation resulting in marginally enhanced leukemia control. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of NFAT-driven T-cell dysfunction characterized by compensatory upregulation of NR4A3 and multiple other genes encoding exhaustion-related transcription factors hampered effector function in solid tumors. PRDM1 and NR4A3 combined ablation skewed CAR T-cell phenotypes away from TIM3+CD8+ and toward TCF7+CD8+ to counter exhaustion of tumor-infiltrating CAR T-cells and improve in vivo antitumor responses, effects that were not achieved with BLIMP1 or NR4A3 single disruption alone. These data reveal a novel molecular targeting strategy to enrich stem-like CAR T-cells resistant to exhaustion and underscore dual inhibition of PRDM1/NR4A3 expression or activity as a promising approach to advance adoptive cell immuno-oncotherapy.

2022-08-04 | GSE210264 | GEO