The Journal of Clinical Investigation (Sep 2022)

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

  • Jani Huuhtanen,
  • Mette Ilander,
  • Bhagwan Yadav,
  • Olli M.J. Dufva,
  • Hanna Lähteenmäki,
  • Tiina Kasanen,
  • Jay Klievink,
  • Ulla Olsson-Strömberg,
  • Jesper Stentoft,
  • Johan Richter,
  • Perttu Koskenvesa,
  • Martin Höglund,
  • Stina Söderlund,
  • Arta Dreimane,
  • Kimmo Porkka,
  • Tobias Gedde-Dahl,
  • Björn T. Gjertsen,
  • Leif Stenke,
  • Kristina Myhr-Eriksson,
  • Berit Markevärn,
  • Anna Lübking,
  • Andreja Dimitrijevic,
  • Lene Udby,
  • Ole Weis Bjerrum,
  • Henrik Hjorth-Hansen,
  • Satu Mustjoki

Journal volume & issue
Vol. 132, no. 17

Abstract

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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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