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STING activation improves T-cell-engaging immunotherapy of acute myeloid leukemia

ABSTRACT: STING activation improves T-cell-engaging immunotherapy of acute myeloid leukemia

PROVIDER: PRJNA1065460 | ENA |

REPOSITORIES: ENA

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STING activation improves T-cell-engaging immunotherapy of acute myeloid leukemia

Project description:T-cell recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising response rates, early clinical trials have failed to demonstrate durable responses. Here we investigated whether activation of the innate immune system through stimulator of interferon genes (STING) can enhance target-cell killing by a BsAb targeting CD33 (CD33 BiTE® molecule). Indeed, we show that cytotoxicity against AML mediated by the CD33 BiTE molecule AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic GMP–AMP (cGAMP). We used invitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR–Cas9 knockout experiments to investigate the enhancing effect of cGAMP on the cytotoxicity of AMG330 against AML. Mechanistically, activated T cells prime target AML cells to STING activation through their effector cytokines interferon-gamma (IFNγ) and tumor necrosis factor (TNF), leading to increased production of typeI interferons and induction of interferon-stimulated genes. This feeds back to the T cells, leading to a further increase in effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP in enhancing AMG330-mediated lysis. As such, we establish a key role for IFNγ in AMG 330-mediated cytotoxicity against AML cells, as well as in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist.

2025-02-01 | GSE253398 | GEO

Biodegradable Nanoparticles Induce cGAS/STING-dependent Reprogramming of Myeloid Cells to Promote Tumor Immunotherapy

Project description:Biodegradable Nanoparticles Induce cGAS/STING-dependent Reprogramming of Myeloid Cells to Promote Tumor Immunotherapy

| PRJEB51888 | ENA

The effect of myeloid STING knockout on gene expression in colitic mice

Project description:Myeloid-derived STING has been recognized to play a vital role in mediating the development of colitis. We here report that myeloid-specific knockout of STING in adult mice ameliorates DSS-induced acute colitis through inhibiting macrophage maturation, reducing DC cell activation, and suppressing pro-inflammatory Th1 and Th17 cells.

2024-08-14 | GSE252100 | GEO

Autophagy engaging and non-engaging hematopoietic stem cells

Project description:Autophagy engaging and non-engaging hematopoietic stem cells

| PRJNA958188 | ENA

The effect of myeloid STING knockout after tumor formation on gene expression in AOM/DSS-induced CAC mice

Project description:Myeloid-derived STING has been recognized to play a vital role in mediating the development of colitis-associated carcinoma (CAC). We here report that myeloid-specific knockout of STING after tumor formation enhanced tumor growth by modifying the tumor microenvironment to a more immunologically inactive state. Pathways related to antigen presentation, macrophage and DC activation, T cell chemotaxis and activation, T cell-mediated cytotoxicity and other immune responses to tumor cells were all inhibited by lateral myeloid STING kncckout after tumor formation.

2024-08-14 | GSE252099 | GEO

C9orf72 in myeloid cells suppresses STING-induced inflammation

Project description:C9orf72 in myeloid cells suppresses STING-induced inflammation

| PRJNA637768 | ENA

RNASeq analysis of Myeloid Derived Suppressor Cells (MDSCs) from MC38 syngeneic mice to study their role on tumour intrinsic pathways (STING/IFN) for driving ceralasertib (AZD6738) efficacy

Project description:Understanding MoA of ceralasertib (AZD6738) in driving efficacy through immune regulation via polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC) and monocytic-myeloid derived suppressor cells (M-MDSC) on tumour intrinsic pathways (STING/IFN) for AZD6738 driven efficacy. Animals were treated only for 7 days and left for further 7 days without treatment. We compared cells against Vehicle and spleen derived ( naive) as a positive control.

2024-01-30 | E-MTAB-13707 | biostudies-arrayexpress

C9orf72 in myeloid cells suppresses STING-induced inflammation

Project description:In this study we report that loss of C9orf72 expression in myeloid cells drives STING/type I interferon mediated autoimmunity and enhanced tumor immunity in mice. Additionally, we show that the immunophenotypic signature identified in C9orf72-/- mice is present in blood derived macrophages, whole blood and autopsy brain tissue from C9orf72 repeat expansion ALS/FTD patients.

2020-09-03 | GSE151936 | GEO

Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers

Project description:Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis.

2025-01-14 | GSE283208 | GEO

Inflammation-Driven Carcinogenesis is Mediated through STING [MEFs]

Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), STING deficient MEFs (SKO), Trex1 deficient MEFs (TKO), and both STING and Trex1 deficient MEFs (STKO) treated with DMBA and examined cytokine production by these cells.

2014-05-31 | E-GEOD-57603 | biostudies-arrayexpress

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