IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia.

Autor:	Huuhtanen J; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland.; Department of Computer Science, Aalto University, Espoo, Finland., Ilander M; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Yadav B; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Dufva OM; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Lähteenmäki H; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Kasanen T; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Klievink J; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Olsson-Strömberg U; Department of Medical Sciences, Uppsala University and Hematology Section, Uppsala University Hospital, Uppsala, Sweden., Stentoft J; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark., Richter J; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden., Koskenvesa P; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland., Höglund M; Department of Medical Sciences, Uppsala University and Hematology Section, Uppsala University Hospital, Uppsala, Sweden., Söderlund S; Department of Medical Sciences, Uppsala University and Hematology Section, Uppsala University Hospital, Uppsala, Sweden., Dreimane A; Department of Medical and Health Sciences, Linköping University, Department of Hematology, County Council of Östergötland, Linköping, Sweden., Porkka K; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland.; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland., Gedde-Dahl T; Department of Hematology, Oslo University Hospital, Rikshospitalet, Oslo, Norway., Gjertsen BT; Department of Internal Medicine, Hematology Section, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway., Stenke L; Department of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden., Myhr-Eriksson K; Department of Internal Medicine, Sunderby Hospital, Luleå, Sweden., Markevärn B; Department of Hematology, Umeå University Hospital, Umeå, Sweden., Lübking A; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden., Dimitrijevic A; Department of Hematology, Odense University Hospital, Odense, Denmark., Udby L; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Bjerrum OW; Department of Hematology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark., Hjorth-Hansen H; Department of Hematology, St. Olavs Hospital, Trondheim, Norway.; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Mustjoki S; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.; Hematology Research Unit Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, Helsinki, Finland.; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2022 Sep 01; Vol. 132 (17).
DOI:	10.1172/JCI152585
Abstrakt:	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.
Databáze:	MEDLINE
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