TET2 Promotes Tumor Antigen Presentation and T Cell-Directed Tumor Cell Cytotoxicity Which is Enhanced by Vitamin C Treatment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA947645 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Immune evasion by tumors is promoted by low T cell infiltration, an immunosuppressive tumor microenvironment, poor T cell activity directed against the tumor, and reduced tumor antigen presentation. We showed previously that tumor expression of the DNA dioxygenase TET2 enhances recruitment of T cells through activating the expression of CXCL9, 10 and 11. Vitamin C treatment was shown to increase these effects in a TET2 dependent manner. Using scSeq analysis, we show that an additional function for TET2 in tumors is to enhance the expression of genes involved in antigen presentation, including those encoding H-2 MHC proteins, B2M, TAP1, TAPBP, and components of immunoproteasome. Using the B16-OVA melanoma model, we show that antigen expression in tumors is blocked if TET2 expression is eliminated and that vitamin C further promotes tumor antigen presentation in a TET2-dependent manner. Consistently, T cell killing assays demonstrate that effective killing of tumor by antigen-specific T cells requires TET2 expression in the tumor cells. Analysis of patient tumor samples indicates that TET2 activity, as measured through 5hmC levels, correlates directly with expression of antigen-presentation gene expression and with patient outcomes.
2024-05-16 | GSE227998 | GEO
Project description:Current cancer immunotherapies are assumed to improve infiltration and cytotoxicity of immune cells in the tumor. However, tumor cells have developed a variety of resistance mechanisms to suppress the MHC class I antigen presentation, and thereby impair the cytotoxicity of CD8+ T cells. Here, we identified Mal2 as a key player that mediates the turnover of the antigen-MHC-I complex and reduce the antigen presentation on tumor cells. Mal2 promotes the endocytosis of tumor antigen via direct interaction with the MHC-I complex and endosome-associated Rab5/7. In mouse and human breast tumor models, inhibition of Mal2 profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that Mal2 is a potential target for breast cancer immunotherapy.
2020-01-23 | GSE144099 | GEO
Project description:One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine thatpotetiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I) that significantly promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex,as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigenprocessing activity of immunoproteasome, leading to enhanced major histocompatibility class I(MHC-I)-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation, empowers T-cell cytotoxicity, and thus elevates the tumorresponse to immunotherapy.
2021-03-31 | GSE171158 | GEO
Project description:The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling. This accession concerns 46 transcriptomic experiments with Affymetrix Mouse 430-2 array..
2019-12-12 | E-MTAB-8501 | biostudies-arrayexpress
Project description:Inactivation of tumor infiltrating lymphocytes (TILs) is one of the limiting factors of anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironment. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further reveals that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs during anti-tumor immunity, and that Tet2 inactivation could benefit anti-tumor immunity and suppress tumor growth.
2021-04-20 | GSE152496 | GEO
Project description:TET2-mediated mRNA in tumor immunity [m5C]
| PRJNA963841 | ENA
Project description:TET2 deficiency subverts tumor immunity [model 3]
| PRJNA851067 | ENA
Project description:Host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a pivotal role of the DNA demethylase and tumor suppressor TET2 played in host antitumor immunity. Deletion of Tet2 dramatically elevated the IL-6 level in Tet2-/- mice upon tumor challenge. The elevated IL-6 greatly stimulated the immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn significantly reduced CD8+ T cells upon tumor challenge. Consequently, systematic knockout of the Tet2 in mice led to accelerated syngeneic tumor growth, which was constrained by anti-PD-1 blockade. Removal of G-MDSCs by the anti-mouse Ly6g Ab restored the numbers of CD8+ T cells in Tet2-/- mice and rebooted their anti-tumor activity. Importantly, anti-IL-6 Ab treatment blocked the expansion of G-MDSCs and inhibited syngeneic tumor growth. Collectively, these findings reveal a TET2-mediated IL-6/G-MDSC/CD8+ T immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism of TET2 for tumor suppression.
2020-08-04 | GSE144787 | GEO
Project description:Tet2 inactivation enhances the anti-tumor activity of tumor-infiltrating lymphocytes
| PRJNA639537 | ENA
Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride