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, and Markevärn, Berit
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. [ABSTRACT FROM AUTHOR]