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Transcriptome-wide identification of STING agonist programed B cells

ABSTRACT: Transcriptome-wide identification of STING agonist programed B cells

PROVIDER: PRJNA819428 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18465617_1.fastq.gz	Fastqsanger.gz
	SRR18465617_2.fastq.gz	Fastqsanger.gz
	SRR18465618_1.fastq.gz	Fastqsanger.gz
	SRR18465618_2.fastq.gz	Fastqsanger.gz
	SRR18465619_1.fastq.gz	Fastqsanger.gz

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Transcriptome-wide identification of STING agonist programed B cells

Project description:We employed RNA-seq to study the transcriptomic change in B lymphocytes in response to STING agonist. Transcriptomic analysis of wild type and TMEM173–/– B cells stimulated with STING agonist revealed that the inflammatory response pathway enriched in 3'3'-cGAMP treated WT B cells but lacking in Tmem173-/-B cells comprised of a cluster containing inhibitory regulators, provoking STING signal to evade immune surveillance by inducing an immunosuppressive B cell population.

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A Phosphotriester-Masked Dideoxy-cGAMP Derivative as a Cell-Permeable STING Agonist

Project description:2’3’-cyclic GMP-AMP (cGAMP) is a cyclic dinucleotide second messenger in which guanosine and adenosine are connected by one 3’-5’ and one 2’-5’ phosphodiester linkage. It is formed in the cytosol upon detection of pathogenic DNA by the enzyme guanosine-monophosphate-adenosine monophosphate synthase (cGAS). cGAMP subsequently binds to the adaptor protein stimulator of interferon genes (STING) to elicit an innate immune response leading to the production of type I interferons and cytokines. STING agonists are a highly promising avenue for an immuno-oncological anticancer therapy. A particular challenge with cyclic dinucleotide STING agonists are the two negative charges of the phosphodiester linkages, which strongly reduce the ability of such compounds to penetrate cell membranes. The development of cell-permeable STING agonists that can stimulate the immune system to enhance their anticancer potency is currently of utmost importance in the field. Here, we report the development of a dideoxy derivative of cGAMP as a phosphotriester prodrug, where the negative charge of the phosphate backbone has been masked with a thioester. We found that this thioester-protected compound features a dramatic increase in its cellular potency that rises from EC50 = 5 µM to 25 nM. The new compound is envisioned to enable an efficient STING-agonist-based anticancer therapy.

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