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IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia
Jani Huuhtanen, … , Henrik Hjorth-Hansen, Satu Mustjoki
Jani Huuhtanen, … , Henrik Hjorth-Hansen, Satu Mustjoki
Published September 1, 2022
Citation Information: J Clin Invest. 2022;132(17):e152585. https://doi.org/10.1172/JCI152585.
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Research Article Hematology Immunology

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

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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.

Authors

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

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Figure 1

The landscape of CP-CML patients’ immune repertoire during dasatinib plus IFN-α combination treatment is dominated by NK and CD8+ T cells.

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The landscape of CP-CML patients’ immune repertoire during dasatinib plu...
(A) Schematics showing the outline of the study. Samples were taken at 0-, 3-, 12-, and 24-month time points. Figure was created with BioRender.com. (B) UMAP projection showing the scRNA-seq profiles from all 100,000 cells (n = 4, 3 time points) in the study, colored by inferred cluster. (C) Dot plot showing the expression of selected canonical markers aiding in cluster annotation. The color of the dot corresponds to the average expression (z score) of the gene and the size of the dot corresponds to the percentages of cells in the cluster expressing the gene. (D) The same UMAP projection as in B showing the cell densities at different time points. (E) The immune repertoire evenness at different time points calculated from scRNA-seq clusters with Gini index (higher values correspond to more skewed repertoires). (F) PCA plot from the flow cytometry–profiled samples (n = 40 patients, 4 time points). (G) Box-and-whisker plot (defined in the Methods) showing the position of samples in PC2. P value was calculated with the Kruskal-Wallis test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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