Effect of MINK1 deficiency on gene expression in CD8+ OT-I TILs
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE319767 | GEO | 2026/05/14
REPOSITORIES: GEO
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Project description:The accumulation of ROS in the tumor microenvironment is a major driving factor for immunosuppression. While its detrimental effects on T cell activation are recognized, the precise molecular mechanisms remain unclear. In this study, we identify MINK1 as a ROS-responsive kinase in regulating CD8+ T cell-mediated anti-tumor immunity. We found that MINK1 ablation enhances the effector function of intratumoral CD8⁺ T cells by facilitate CD8+ effector T-cell differentiation, thereby enabling sustained tumor control. Mechanistically, MINK1 interacts with LATS1 and activates the Hippo pathway, thereby suppressing cytotoxic gene expression and inhibiting CD8+ T cell differentiation into effector subtypes. Finally, we proved that targeting MINK1 in both CAR-T and TCR-T cells could improve anti-tumor CD8+ T cell response in solid tumor models. Pharmacological inhibition of MINK1 also enhances anti-tumor immune responses in mice. Thus, this work uncovered MINK1 as a pivotal driver for CD8+ T cell dysfunction in tumors and highlights its potential as a therapeutic target for enhancing cancer immunotherapy.
2026-05-14 | GSE319766 | GEO
Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | MassIVE
Project description:Metabolic reprograming towards aerobic glycolysis is a pivotal mechanism that shapes immune responses. While deregulated T cell metabolism is associated with autoimmune diseases, metabolic deficiency contributes to T cell exhaustion in tumor microenvironment. Here we describe a posttranslational mechanism of glycolysis regulation mediated by the NF-kB-inducing kinase (NIK). NIK deficiency impairs glycolysis induction, rendering CD8 effector T cells hypofunctional with features of exhaustion in tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8 T cell metabolism and prevents exhaustion, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. Interestingly, although NIK is known as a kinase mediating activation of noncanonical NF-kB, NIK regulates T cell metabolism via an NF-kB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK deficiency causes autophagic degradation of HK2, at least in part due to aberrant ROS accumulation. NIK phosphorylates, and maintains the activity of, glucose-6-phosphate dehydrogenase (G6PD), an enzyme mediating production of the antioxidant NADPH required for preventing ROS accumulation and oxidative stress. We provide genetic evidence that the G6PD-NADPH redox system has a vital role in regulating HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a posttranslational mechanism of metabolic regulation involving the G6PD-NADPH redox system.
2020-10-02 | GSE155576 | GEO
Project description:CD8 T cells play a central role in immune responses against pathogens and cancer; however, CD8 T cells are typically rendered hypofunctional in tumor microenvironment due to tolerance to cancer cells and functional exhaustion. How to overcome CD8 T cell tolerance and stimulate strong antitumor responses has become an important issue for cancer immunotherapy 1,2. Here we identified the atypical deubiquitinase Otub1 as a pivotal regulator of CD8 T cell self-tolerance and antigen-stimulated responses. T cell-specific deletion of Otub1 in mice breaks CD8 T cell self-tolerance and promotes the metabolic reprograming and effector functions of activated CD8 T cells, resulting in profoundly stronger immunity against infections and tumorigenesis. The Otub1 deletion also synergizes with an immune checkpoint inhibitor in inducing tumor rejection and greatly increases the efficiency of an adoptive T cell transfer model of cancer immunotherapy. In line with these findings, the expression level of Otub1 is inversely associated with the abundance of CD8 effector T cell signature gene expression and patient survival in human melanoma. Mechanistically, Otub1 negatively regulates activation of AKT, a kinase that integrates the T cell receptor (TCR) and cytokine signals and mediates CD8 T cell metabolism and effector functions. Otub1 deficiency greatly promotes AKT activation by both the TCR signal and the immunostimulatory cytokine IL-15. Otub1 inhibits AKT ubiquitination and, thereby, suppresses its interaction with the membrane lipid phosphoinositol 3,4,5 triphosphate required for membrane translocation. These results demonstrate a ubiquitin-dependent mechanism that controls CD8 T cell responses and implicate Otub1 as a potential therapeutic target for cancer immunotherapy.
2019-05-16 | GSE126777 | GEO
Project description:To elucidate the mechanism by which DADA enhances the CD8+ T cell anti-tumor immune responses, we performed signal-cell RNA-sequencing (scRNA-seq) on tumor-infiltrating CD45+ T cells isolated from ctrl- or DADA-treated MC38-bearing mice.In this study, we found that diisopropylamine dichloroacetate (DADA) enhances CD8⁺ T cell-mediated anti-tumor immunity and promotes the accumulation of Tpex cells in the tumor microenvironment. Mechanistically, DADA promotes the conversion of pyruvate to acetyl-CoA by inhibiting pyruvate dehydrogenase kinase, thereby increasing oxidative phosphorylation (OXPHOS) levels and mitochondrial fitness, and ultimately enhancing the stemness of CD8⁺ T cells. In mouse models, DADA treatment significantly improves the efficacy of PD-1 blockade. Furthermore, the addition of DADA to the in vitro expansion system of chimeric antigen receptor (CAR)-T cells confers stemness characteristics to the cells, thereby enhancing their anti-tumor efficacy.
2026-05-20 | GSE317913 | GEO
Project description:The Pim kinase family is critically involved in tumorigenesis, yet its function in primary T cells remains poorly understood. We previously reported that Pim2 negatively regulates T-cell responses to alloantigen. To investigate how Pim2 impacts anti-tumor immunity of CD8 T cells, we generated Pim2-/- strains bearing tumor-antigen-specific T cells and performed adoptive T-cell therapy (ACT) against established tumor. We found that Pim2 restricts effector differentiation and persistence of CD8 T cells. As a result, Pim2-/- CD8 T cells exhibited greater potency than WT cells in controlling tumor growth across various cancer models. Mechanistically, Pim2 phosphorylates and inhibits its downstream target Vprbp, a kinase that phosphorylates and stabilizes Ezh2. Consistently, Pim2 deficiency increased Ezh2 expression and H3K27 trimethylation in CD8 T cells. Elevated Ezh2 activity in Pim2-/- CD8 T cells supported progenitor-like/memory differentiation within lymphoid organs. Furthermore, Pim2 deficiency diminished autophagy in CD8 T cells, thereby promoting glycolytic metabolism to drive effector T-cell differentiation in the tumor microenvironment (TME). In human T cells, silencinge Pim2 increased cytokine production and effector differentiation. A Pim2-specific inhibitor improved murine T-cell immunity against melanoma and increased the activity of human melanoma-specific T cells and CD19 CAR-T cells. Taken together, the current work reveals novel and compelling evidence to support Pim2 as a promising therapeutic target for improving cancer immunotherapy through enhancing effector differentiation and persistence of T cells.
2026-01-08 | PXD059837 | Pride
Project description:Radiotherapy (RT) destroys tumor cells, which may lead to release of antigens and immune-activating signals. In this way, RT may act as an in situ vaccine and kick-start a T-cell response against the tumor. Immunotherapy enhances tumor-specific T-cell responses. Combination of radiotherapy and immunotherapy (radio-immunotherapy (RIT)) can therefore be expected to synergize in inducing and sustaining systemic anti-tumor T-cell responses. However, in the clinic, systemic combined responses between radiotherapy and immunotherapy are rarely observed, as the effect of RIT combinations on ‘abscopal’ tumors outside the radiotherapy field are not (yet) greater than the effect of immunotherapy alone. In order to define potential bottlenecks in the tumor micro-environment that impede CD8 T cell activity, we harvested irradiated and non-irradiated tumors from the same mice that were treated with RIT (10 Gy RT, anti-CD137 and anti-PD1). From these tumors, effector (CD43+) CD8 T cells, ‘other’ hematopoietic (CD45+) cells and tumor/stromal (CD45-) were sorted and RNA sequencing was performed to identify differences between these cell populations in the irradiated and non-irradiated tumors that could explain the lack of T cell activity in the non-irradiated tumor.
2019-02-12 | E-MTAB-6914 | biostudies-arrayexpress
Project description:<p>Background: The objective response rate of anti-programmed death receptor 1 (PD-1) immunotherapy in hepatocellular carcinoma (HCC) remains limited. The tumor immunosuppressive microenvironment mediated by regulatory T cells (Tregs) is a key bottleneck. The traditional Chinese medicine (TCM) compound Fuzheng Jiedu Xiaoji Formula (FZJDXJ) has been proven to improve the clinical efficacy of adjuvant therapy for HCC and remodel the tumor immunosuppressive microenvironment, yet its sensitizing effect and underlying mechanism on PD-1 inhibitors remain unclear.</p><p>Methods: A total of 55 clinical patients were enrolled, who received either immunotherapy alone or FZJDXJ combined with immunotherapy for 3 cycles. The 1-year efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and peripheral immune responses were analyzed by multicolor flow cytometry. A Hepa1-6 orthotopic HCC mouse model was established and divided into four groups: model group, anti-PD-1 monotherapy group, FZJDXJ monotherapy group, and FZJDXJ combined with anti-PD-1 group. Tumor growth, as well as the function of Tregs and CD8+T cells in the periphery and tumor infiltrates, were assessed. Transcriptomic and metabolomic analyses were conducted to explore the molecular mechanisms and metabolic characteristics of the tumor microenvironment, with in vitro for validation.</p><p>Results: In the clinical cohort, the 1-year disease control rate (DCR) of the combination therapy group was significantly increased by 28.5% (83.3% vs. 54.8%, p = 0.026), and the incidence of adverse events was reduced by 36.3% (25% vs. 61.3%, p = 0.010) compared with the immunotherapy-alone group. Multicolor flow cytometry confirmed that the combination therapy significantly decreased the proportion of peripheral Tregs and increased the ratio of tissue-resident memory CD8+T cells (TRM) with effector function. In HCC-bearing mice, the combination therapy sensitized the anti-tumor effect of anti-PD-1 treatment, ameliorated immune-related hepatitis and nephritis induced by immunotherapy, enhanced the proportion, cytotoxicity, and proliferation of peripheral and tumor-infiltrating CD8+T cells, and markedly reduced the infiltration and proliferation of Tregs. Multi-omics analyses revealed that the combination therapy significantly downregulated the DHCR7-TFR1 signaling pathway, inhibiting lipotoxicity caused by excessive lipid accumulation in Tregs, which was identified as the central mechanism of the combination therapy for HCC. In vitro confirmed that FZJDXJ containing serum suppressed the activation of the DHCR7-TFR1 signaling pathway, inhibited excessive lipid accumulation in Tregs (detected by BODIPY493/503-FITC, Liperfluo, ROS, and MitoSOX), and attenuated the immunosuppressive capacity of Tregs and their secretion of TGF-βand IL-10 cytokines.</p><p>Conclusion: FZJDXJ enhances the efficacy of anti-PD-1 therapy for HCC by inhibiting Treg cholesterol metabolic reprogramming and lipotoxicity, thereby relieving the excessive immunosuppression of CD8+T cells by Tregs. This study provides a novel mechanism and clinical evidence for the combination of TCM compounds with immunotherapy for HCC.</p>
2025-12-05 | MTBLS13458 | MetaboLights
Project description:DNA hypomethylating agents (HMAs) induce Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. Yet, the direct effects of HMAs in immune cells remains less clear. Here, we demonstrate that HMA treatments can directly modulate the anti-tumor response and effector function of CD8+ T-cells. In vivo HMA treatment promotes CD8+ T-cell tumor infiltration and supresses tumor growth via CD8+ T-cell dependent activity. HMAs enhances primary human CD8+ T-cells activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T-cell activation related transcriptional networks, culminating with over-activation of NFATc1 short-isoforms. Mechanistically, demethylation of an intragenic CpG Island immediately downstream to the 3'UTR of the short isoform was associated with anti-sense transcription and alternative polyadenylation of NFATc1 short-isoforms. High-dimensional single-cell mass cytometry (CyTOF) analyses reveal a selective effect of HMAs on a subset of human CD8+ T-cell subpopulations, resulting in an increase in both number and abundance of a granzymeBhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.
2021-02-08 | GSE151917 | GEO
Project description:Antigen-specific CD8+ T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet, the mechanisms of lymphocyte transit remain poorly defined. We find that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression on effector CD8+ T cells. Only high affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention. A diverse repertoire of functional tumor-specific CD8+ T cells exit the tumor, thereby limiting tumor control. CXCR4 inhibition and loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. Strategies that limit T cell egress, therefore, provide a new tool to boost the response to immunotherapy.
2023-01-20 | GSE218455 | GEO