Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB18653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR615207.fastq.gz | Fastqsanger.gz |
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Project description:Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrate that delivery of class I histone deacetylase inhibitor, MS-275, promotes sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We find that MS-275 alters the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ dendritic cells and depletion of regulatory T cells. Activated endogenous CD8+ T cell responses against non-target tumor antigens was critically required for the prevention of tumor recurrence. Importantly, MS-275 alters the immunodominance hierarchy by directing epitope spreading towards endogenous retroviral tumor-associated antigen, p15E. Our data suggest that MS-275 multi-mechanistically improves epitope spreading to promote long-term clearance of solid tumors.
2021-07-03 | GSE179337 | GEO
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
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
Project description:Non-Invasive Manipulation of Intratumoral Genome Editing Potentiates Adoptive T-Cell Therapy against Solid Tumors
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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.
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Project description:This phase I pilot trial studies the side effects of cluster of differentiation 8 (CD8)+ T cells in treating patients with gastrointestinal tumors that have spread to other places in the body. Tumor cells and blood are used to help create an adoptive T cell therapy, such as CD8+ T cell therapy, that is individually designed for a patient and may help doctors learn more about genetic changes in the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving CD8+ T cell therapy and pembrolizumab may work better in treating patients with gastrointestinal tumors.
| 2214011 | ecrin-mdr-crc
Project description:CD8+ T lymphocytes mediate potent immune responses against tumor, but the role of human CD4+ T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26neg T cells possess a regulatory phenotype, CD26int T cells are mainly naive and CD26high T cells appear terminally differentiated and exhausted. Paradoxically, CD26high T cells persist in and regress multiple solid tumors following adoptive cell transfer. Further analysis revealed that CD26high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (β-catenin and Lef1). These properties license CD26high T cells with a natural capacity to traffic to, regress and survive in solid tumors. Collectively, these findings identify CD4+ T cell subsets with properties critical for improving cancer immunotherapy
2017-11-11 | GSE106726 | GEO
Project description:Mitochondria regulate T cell functions and response to cancer immunotherapy. We show that pharmacologically induced PKM2 activation enhances mitochondria-dependent effector functions in mouse and human CD8 T cells and CAR-T cells. Multi-omics analysis and 13C-glucose tracer experiments showed that PKM2 activation alters one-carbon metabolism with decreased levels of methionine leading to hypomethylation of mitochondrial and nuclear DNA and enhanced expression of genes supporting mitochondrial biogenesis and respiratory complex formation in CD8 T cells. Functionally, PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells after adoptive cell therapy. Using preclinical melanoma and colon cancer models, we found that PKM2-agonist induced CD8 T cell-dependent anti-tumor responses that synergized with PD1 blockade therapy. Immunologically, PKM2 agonists resulted in enhanced activation and decreased exhaustion of effector T cells while reducing the numbers of suppressive FoxP3+ Treg cells in the tumor microenvironment. Anti-PD1 combination further enhanced the frequency and activation of tumor specific CD8 T cells in the tumors. Together, we show that PKM2 agonism modulates mitochondrial structure and function, leading to enhanced effector functions of cytotoxic lymphocytes. Hence, targeting PKM2 via pharmacologically available small molecules can be a clinically viable strategy for the enhancement of therapeutic potential of in-situ immune responses, adoptive cell therapy, and immune checkpoint blockade therapy
2025-05-01 | GSE289772 | GEO
Project description:Mitochondria regulate T cell functions and response to cancer immunotherapy. We show that pharmacologically induced PKM2 activation enhances mitochondria-dependent effector functions in mouse and human CD8 T cells and CAR-T cells. Multi-omics analysis and 13C-glucose tracer experiments showed that PKM2 activation alters one-carbon metabolism with decreased levels of methionine leading to hypomethylation of mitochondrial and nuclear DNA and enhanced expression of genes supporting mitochondrial biogenesis and respiratory complex formation in CD8 T cells. Functionally, PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells after adoptive cell therapy. Using preclinical melanoma and colon cancer models, we found that PKM2-agonist induced CD8 T cell-dependent anti-tumor responses that synergized with PD1 blockade therapy. Immunologically, PKM2 agonists resulted in enhanced activation and decreased exhaustion of effector T cells while reducing the numbers of suppressive FoxP3+ Treg cells in the tumor microenvironment. Anti-PD1 combination further enhanced the frequency and activation of tumor specific CD8 T cells in the tumors. Together, we show that PKM2 agonism modulates mitochondrial structure and function, leading to enhanced effector functions of cytotoxic lymphocytes. Hence, targeting PKM2 via pharmacologically available small molecules can be a clinically viable strategy for the enhancement of therapeutic potential of in-situ immune responses, adoptive cell therapy, and immune checkpoint blockade therapy
2025-05-01 | GSE289771 | GEO
Project description:This ordinary differential equation model simulating the interactions between tumor and immune cells is detailed in the publication:
Ahmed M. Makhlouf, Lamiaa El-Shennawy, Hesham A. Elkaranshawy, "Mathematical Modelling for the Role of CD4+T Cells in Tumor-Immune Interactions", Comput Math Methods Med. 2020 Feb 19;2020:7187602.
doi: 10.1155/2020/7187602
Comment:
This no treatment model is described by equations 1-7 of the publication manuscript.
Abstract:
Mathematical modelling has been used to study tumor-immune cell interaction. Some models were proposed to examine the effect of circulating lymphocytes, natural killer cells, and CD8+T cells, but they neglected the role of CD4+T cells. Other models were constructed to study the role of CD4+T cells but did not consider the role of other immune cells. In this study, we propose a mathematical model, in the form of a system of nonlinear ordinary differential equations, that predicts the interaction between tumor cells and natural killer cells, CD4+T cells, CD8+T cells, and circulating lymphocytes with or without immunotherapy and/or chemotherapy. This system is stiff, and the Runge–Kutta method failed to solve it. Consequently, the “Adams predictor-corrector” method is used. The results reveal that the patient’s immune system can overcome small tumors; however, if the tumor is large, adoptive therapy with CD4+T cells can be an alternative to both CD8+T cell therapy and cytokines in some cases. Moreover, CD4+T cell therapy could replace chemotherapy depending upon tumor size. Even if a combination of chemotherapy and immunotherapy is necessary, using CD4+T cell therapy can better reduce the dose of the associated chemotherapy compared to using combined CD8+T cells and cytokine therapy. Stability analysis is performed for the studied patients. It has been found that all equilibrium points are unstable, and a condition for preventing tumor recurrence after treatment has been deduced. Finally, a bifurcation analysis is performed to study the effect of varying system parameters on the stability, and bifurcation points are specified. New equilibrium points are created or demolished at some bifurcation points, and stability is changed at some others. Hence, for systems turning to be stable, tumors can be eradicated without the possibility of recurrence. The proposed mathematical model provides a valuable tool for designing patients’ treatment intervention strategies.
2024-09-02 | BIOMD0000001042 | BioModels