T cell intrinsic immunomodulatory effects of TAK-981 in chronic lymphocytic leukemia patient derived T cells
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PROVIDER: PRJNA862282 | ENA |
REPOSITORIES: ENA
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Project description:SUMOylation, a post-translational modification of the ubiquitin family plays a critical role in the regulation of proteins function and fate. TAK-981 (Subasumstat) is a first-in-class inhibitor of the SUMO-activating enzyme used in various phase I/II clinical trials for solid tumors and lymphomas. In addition to its direct cytotoxic effect on cancer cells, TAK-981 activates anti-tumor immune response. We show here that TAK-981 activates human natural killer cells. TAK-981 mostly regulates genes involved in inflammation and immune response, in particular those related to the type-I and type-II interferon pathway.
2024-02-28 | GSE255279 | GEO
Project description:Acute Myeloid Leukemias (AML) are severe hematomalignancies with dismal prognosis. The post-translational modification SUMOylation plays key roles in leukemogenesis and AML response to therapies. Here, we show that TAK-981 (subasumstat), a first-in-class SUMOylation inhibitor, is endowed with potent anti-leukemic activity in various preclinical models of AML. TAK-981 targets AML cell lines and patient blast cells in vitro and in vivo in xenografted mice with minimal toxicity on normal hematopoietic cells. Moreover, it synergizes with 5-azacitidine (AZA), a DNA-hypomethylating agent now used in combination with the BCL-2 inhibitor venetoclax to treat AML patients unfit for standard chemotherapies. Interestingly, TAK-981+AZA combination shows higher anti-leukemic activity than AZA+venetoclax combination both in vitro and in vivo, at least in the models tested. Mechanistically, TAK-981 potentiates the transcriptional reprogramming induced by AZA, promoting apoptosis, alteration of the cell cycle and differentiation of the leukemic cells. In addition, TAK-981+AZA treatment induces many genes linked to inflammation and immune response pathways. In particular, this leads to the secretion of type I interferon (IFN-I) by AML cells. Finally, TAK-981+AZA induces the expression of Natural Killer (NK)-activating ligands (MICA/B) and adhesion proteins (ICAM-1) at the surface of AML cells. Consistently, TAK-981+AZA-treated AML cells activate NKs and increase their cytotoxic activity. Targeting SUMOylation with TAK-981 may thus be a promising strategy to both sensitize AML cells to AZA and reduce their immune-escape capacities.
2023-08-29 | GSE212330 | GEO
Project description:SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor TAK-981 in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated synergistic antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.
2024-04-24 | GSE185841 | GEO
Project description:Transcriptome analysis of TAK981 or DMSO pre-treated chronic lymphocytic leukemia patient derived T cells upon TCR engagement
2024-07-25 | GSE209744 | GEO
Project description:Intravenous administration of TAK-981 to Balb/c or C57BL/6 mice bearing A20 or B16F10 syngeneic tumors, respectively, resulted in a strong induction of IFN1 pathway genes in peripheral blood leukocytes, spleen and A20 tumor tissues. TAK- 981 dependent upregulation of IFN1 mRNA signature was determined from RNA-Seq data in peripheral blood, spleen and tumor of BALB/c mice bearing A20 tumors. Upregulation of IFN1 ssGSEA scores were calculated in peripheral blood at 4h (P = 0.0011) and 8h (P = 0.0001), in spleen at 4h (P = 0.0002) and 8h (P = 0.0020), and in tumor at 4h (P = 0.0095) and 8h (P = 0.0033) after treatment with the indicated doses of TAK-981. Dose dependent upregulation of IFN1 mRNA signature by TAK-981 was determined from RNA-Seq data in peripheral blood and spleen of C57BL/6 mice bearing B16F10 tumors. Upregulation of IFN1 ssGSEA scores in the blood at 4h (P = 0.001) and 8h (P = 0.0125) and in the spleen at 4h (P = 0.0019) and 8h (P = 0.0796) after treatment with the indicated concentrations of TAK-981. No upregulation of ssGSEA scores was detected in tumors at 4h (P=0.4295) or 8h (P=0.9706) after treatment with TAK-981. P values were calculated by Welch’s ANOVA test.
2021-04-23 | GSE173114 | GEO
Project description:Modest transcriptional changes has been previously observed in solid tumor cell lines in response to inhibition of SUMOylation by ML-792 and here confirmed with TAK-981, lacking a robust induction of IFN1 genes. Comparable modulation of gene expression in HCT116, MDA-MB-231 and Colo-205 cells by TAK-981 and ML-792. Biological triplicates of HCT116, MDA-MB-231 and Colo-205 cells treated with DMSO, 1 μM ML-792 or 1 μM TAK-981 in vitro for 16 h were analyzed by RNA-Seq. The number of differentially expressed genes (DEGs) with false discovery rate corrected p- values of <0.05 and fold-change values greater than 2 are captured. The degree of gene regulation by TAK-981 is plotted against the degree of gene regulation by ML-792 for the union of their DEGs for each cell line. Data are fitted by linear regression after outliers were removed (7 DEGs from Colo- 205, r^2 = 0.951; 2 DEGs from HCT116, r^2 = 0.836; and 2 DEGs from MDA-MB-231, r^2 = 0.971). Limited and comparable upregulation of human IFN1 mRNA signature in Colo-205, and MDA-MB-231 cells, but not in HCT116 cells, following 16h of treatment with 1uM ML-792 or 1uM TAK-981, as determined by human IFN1 ssGSEA gene signature scores. In vitro treatment of the A20, B16F10, CT26 and MC38 mouse tumor cell lines with TAK-981 did not result in induction of the IFN1 pathway. The overall degree of transcriptional modulation by TAK-981 was relatively modest in the mouse tumor cell lines, with only limited overlap observed in the transcriptional responses to TAK-981, as also observed for the human solid tumor cell lines.
2021-04-23 | GSE173116 | GEO
Project description:The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is lower than 8%. PDAC has the characteristics of high-density stroma and a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy. SUMOylation is a reversible post-translational modification required for cell cycle progression. We found that SUMOylation is increased in PDAC patient samples compared to primary pancreatic tissue. TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activation enzyme E1 (SAE), selectively decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. In vivo TAK-981 efficiently limited the tumor burden in the KPC3 syngeneic mouse model without evidence of general toxicity. Interestingly, we found that TAK-981 modulates the immune system, up-regulating CD8+ T cells, NK cells and down-regulating B cells in peripheral blood, spleen, lymph nodes. Treatment of mouse primary T cells ex vivo with TAK-981 activated STAT1, the key transcription factor induced by interferon signaling. Our findings indicate that inhibition of the SUMO pathway might be a potential clinical strategy to target PDAC by inhibiting tumor cell division and activating anti-tumor immunity.
2022-01-10 | PXD024521 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC. We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activating enzyme E1 (SAE) could be used to treat a preclinical syngeneic PDAC mouse model. We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared to normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumor burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and NK cells but transiently decreased B cell numbers in peripheral blood, spleen and lymph nodes. ScRNA sequencing revealed activation of the interferon response upon TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes. Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumor immunity by inducing interferon signaling.
2022-01-11 | GSE189576 | GEO
Project description:Single cell RNA-Seq analysis of A20 tumors indicated that the IFN1 signature was derived primarily from monocytes and T cells, not the B cell population which includes A20 tumor cells. Single cell RNA-Seq analysis characterized the effect of TAK-981 on B cells (n=4513, includes both A20 B lymphoma tumor cells and WT B cells), erythrocytes (n=238), monocytes (n=85) and T cells (n=107) from A20 tumors responding to treatment with TAK-981. Tumors were harvested 8 h after treatment of A20 tumor-bearing Balb/c mice with either vehicle or 7.5 mg/kg TAK-981 and subjected to scRNA-Seq.
2021-04-23 | GSE173117 | GEO