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Huuhtanen, Jani; Ilander, Mette; Yadav, Bhagwan; Dufva, Olli M.J.; Lähteenmäki, Hanna; Kasanen, Tiina; Klievink, Jay; Olsson-Strömberg, Ulla; Stentoft, Jesper; Richter, Johan; Koskenvesa, Perttu; Höglund, Martin; Söderlund, Stina; Dreimane, Arta; Porkka, Kimmo; Gedde-Dahl, Tobias; Gjertsen, Björn T.; Stenke, Leif; Myhr-Eriksson, Kristina; Markevärn, Berit; Lübking, Anna; Dimitrijevic, Andreja; Udby, Lene; Bjerrum, Ole Weis; Hjorth-Hansen, Henrik; Mustjoki, Satu
The Journal of clinical investigation, 09/2022, Letnik: 132, Številka: 17Journal Article
In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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