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Treatment of granuloma annulare and suppression of pro-inflammatory cytokine activity with tofacitinib

ABSTRACT: Treatment of granuloma annulare and suppression of pro-inflammatory cytokine activity with tofacitinib

PROVIDER: PRJNA667031 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12764504_1.fastq.gz	Fastqsanger.gz
	SRR12764504_2.fastq.gz	Fastqsanger.gz
	SRR12764505_1.fastq.gz	Fastqsanger.gz
	SRR12764505_2.fastq.gz	Fastqsanger.gz
	SRR12764506_1.fastq.gz	Fastqsanger.gz

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Treatment of granuloma annulare and suppression of pro-inflammatory cytokine activity with tofacitinib [scRNA-Seq]

Project description:Treatment of granuloma annulare and suppression of pro-inflammatory cytokine activity with tofacitinib [scRNA-Seq]

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Treatment of granuloma annulare and suppression of pro-inflammatory cytokine activity with tofacitinib [RNA-Seq]

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Treatment of granuloma annulare and suppression of pro-inflammatory cytokine activity with tofacitinib [scRNA-Seq]

Project description:Granuloma annulare (GA) is a common inflammatory cutaneous disorder characterized by macrophage accumulation and activation in the skin. Its pathogenesis is poorly understood and there are no reliably effective treatments. Its potential health implications, if any, are unknown. Using single cell RNA sequencing (scRNAseq) we show that in GA, CD4+ T cells over-produce interferon (IFN)-g resulting in inflammatory polarization of macrophages and in altered extracellular matrix (ECM) production induced by the activity of oncostatin M, an interleukin (IL)-6 family cytokine, on fibroblasts. This mechanism identifies Janus kinase (JAK) inhibition as a potential therapeutic strategy, as both IFN-g and OSM signal via the JAK-STAT pathway. Indeed, treatment of five patients with severe, longstanding GA with tofacitinib (a JAK1/3 inhibitor) resulted in clinical and histologic disease remission in three patients and marked improvement in the other two. Treatment was associated with suppression of pathogenic cytokine activity in the skin and dissolution of macrophages. We also found that severe GA was associated with hypercytokinemia in plasma of patients, and JAK inhibition normalized this hypercytokiemia. Together, our results highlight the constitutive activity of the JAK-STAT pathway in GA as a result of IFN-g and OSM and identify JAK inhibitors as a potential molecularly targeted treatment for this disorder.

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Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment

Project description:The myeloma bone marrow microenvironment drives proliferation of malignant plasma cells and promotes resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells.Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not rescue ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells drive a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.

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