IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia
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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2022-09-01
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en
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16
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Journal of Clinical Investigation, Volume 132, issue 17, pp. 1-16
Abstract
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.Description
Funding Information: The authors would like to acknowledge the patients, study nurses, and other personnel in the clinical centers for their participation in this trial. The trial was supported by a grant from Bristol-Myers Squibb to the Norwegian University of Science and Technology (NTNU). In addition, this work was supported by the Nordic Cancer Union, Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Helsinki Institute of Life Science, Cancer Foundation Finland, the EUTOS project for CML 2018, ERA-Net ERACoSysMed JTC-2 project “prediCt,” the Relander Foundation, and the Finnish Cancer Institute. JH was supported by the Finnish Hematology Association, the Blood Disease Research Foundation, the Helsinki Institute for Life Science, the Biomedicum Helsinki Foundation, the Finnish Medical Foundation, the K. Albin Johansson Foundation, the Kaute Foundation, and the Emil Aaltonen Foundation. Funding Information: Authorship note: JH and MI contributed equally to this work. Conflict of interest: UOS has received honoraria from Incyte. PK has received honoraria from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. JR has received honoraria and research funding from Novartis and Bristol-Myers Squibb and honoraria from Incyte. KP has received honoraria and research funding from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. HHH has received honoraria from Novartis, Bristol-Myers Squibb, and Incyte. SM has received honoraria and research funding from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. Copyright: © 2022, Huuhtanen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: July 6, 2021; Accepted: July 7, 2022; Published: September 1, 2022. Reference information: J Clin Invest. 2022;132(17):e152585. https://doi.org/10.1172/JCI152585. Publisher Copyright: © 2022 American Society for Clinical Investigation. All rights reserved.
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Huuhtanen, J, Ilander, M, Yadav, B, Dufva, O M J, Lähteenmäki, H, Kasanen, T, Klievink, J, Olsson-Strömberg, U, Stentoft, J, Richter, J, Koskenvesa, P, Höglund, M, Söderlund, S, Dreimane, A, Porkka, K, Gedde-Dahl, T, Gjertsen, B T, Stenke, L, Myhr-Eriksson, K, Markevärn, B, Lübking, A, Dimitrijevic, A, Udby, L, Bjerrum, O W, Hjorth-Hansen, H & Mustjoki, S 2022, ' IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia ', Journal of Clinical Investigation, vol. 132, no. 17, e152585, pp. 1-16 . https://doi.org/10.1172/JCI152585