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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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			Action	DRS
	SRR27585737_1.fastq.gz	Fastqsanger.gz
	SRR27585737_2.fastq.gz	Fastqsanger.gz

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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

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Project description:Deep vein thrombosis (DVT), the third most common cause of cardiovascular deaths, is characterized by intravascular clot formation, often accompanied by inflammation. Although the Stimulator of Interferon Genes (STING) signaling pathway has gained recognition as a central mediator of inflammation in the context of infection, cellular stress, and tissue, its intricate involvement in DVT remains enigmatic. Here, we demonstrate that STING inhibition via specific inhibitors or myeloid-specific STING deficiency ameliorated thrombus formation in murine DVT models. Furthermore, our findings uncover a direct interaction between STING and YBX1, resulting in nuclear translocation and enhanced thrombotic inflammation. A synthetic peptide, C-ST16, designed to resemble STING inhibitors, exhibits promising therapeutic potential by effectively reducing thrombus formation and diminishing inflammatory factor expression without the hepatorenal toxicity. Overall, these findings shed light on the interplay between myeloid specific STING-YBX1 and inflammation, offering novel therapeutic insights for DVT management.

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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.

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