Ruxolitinib treatment ameliorates clinical, immunologic, and transcriptomic aberrations in patients with STAT3 gain-of-function disease

Date

2024-01-01

Author

Bayram Catak, Feyza
Catak, Mehmet Cihangir
Babayeva, Royala
Toubia, John
Warnock, Nicholas I.
Celmeli, Fatih
Hafizoglu, Demet
YAKICI, NALAN
Kayaoğlu, Başak
Surucu, Naz
Yalcin Gungoren, Ezgi
Can, Salim
Yorgun Altunbas, Melek
Karakus, Ibrahim Serhat
Kiykim, Ayca
Orhan, Fazil
Bilgic Eltan, Sevgi
Karakoc-Aydiner, Elif
Ozen, Ahmet
Erman, Baran
Gürsel, Mayda
Kok, Chung Hoow
Cildir, Gökhan
Baris, Safa

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Background: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) disease presents with lymphoproliferation, autoimmunity, and failure to thrive. Although Janus kinase inhibitors have alleviated symptoms, their effects on disease pathogenesis remain unclear. Objective: We prospectively investigated the clinical, immunologic, and transcriptomic responses of 4 patients with STAT3 GOF under long-term ruxolitinib treatment. Methods: We conducted clinical and immunologic evaluations at baseline and after ruxolitinib treatment at 3, 8, 12, and more than 12 months. Our assessments included measurement of levels of circulating T follicular helper cells, regulatory T cells, and cytokines, as well as proliferation assays. Furthermore, we investigated the transcriptomic changes with treatment and conducted T-cell receptor sequencing. Results: Ruxolitinib achieved substantial control over the clinical manifestations. Posttreatment evaluations demonstrated a notable increase in naive CD4+ and CD8+ T-cell populations, alongside a significant reduction in effector memory T-cell levels. Additionally, there was a decrease in levels of circulating T follicular helper cells and double-negative T cells. Regulatory T-cell percentages and their canonical markers, which were already reduced before treatment, declined further with ruxolitinib. The treatment did not alter the production of IL-4, IL-17A, IL-10, and IFN-γ cytokines by the CD4+ T cells. Importantly, ruxolitinib effectively normalized the previously dysregulated transcriptome profile in PBMCs, bringing it closer to that of healthy controls. This normalization was most striking in the downregulation of STAT3-targeted genes, interferon-related genes, myeloid cell activation, and cytotoxic effector CD8+ T-cell genes, with effects persisting for up to 12 months. Self-reactive T-cell indices based on T-cell receptor repertoire analysis revealed potential autoreactive cell clones in the patient samples. Conclusion: Ruxolitinib reversed cellular and transcriptomic signatures, enhancing our understanding of the disease's pathophysiology and highlighting essential immunologic markers for precise monitoring.

Subject Keywords

immune dysregulation, immunologic assessment, ruxolitinib, STAT3 GOF, transcriptomic profiling

URI

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85212647103&origin=inward
https://hdl.handle.net/11511/113192

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Graduate School of Natural and Applied Sciences, Article