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

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 2

Dasatinib treatment induces NK and CD8+ T cell maturation.

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Dasatinib treatment induces NK and CD8+ T cell maturation. (A) The diffe...
(A) The differentially abundant (Padj < 0.05, Benjamini-Hochberg–corrected Mann-Whitney) flow cytometry cell populations between 3 months after dasatinib and diagnosis (n = 40). The x axis denotes the log2-transformed fold change (log2FC) of median population abundances. Populations with 2 markers denote the proportion of positive cells from the host population (CD8CD57 = CD57+ cells from CD8+ cells); a single marker (e.g., T cells) denotes the proportion of these cells from lymphocytes; “abs” denotes absolute cell numbers. (B) Selected NK cell subpopulations as percentages of total NK cells analyzed with flow cytometry (n = 40). The P values were calculated with the Mann-Whitney test. (C) UMAP projection of the NK cell clusters identified with scRNA-seq (n = 4) in Figure 1B. The superimposed line represents the predicted maturation trajectory. (D) The same as in C showing the cell densities at different time points. (E) The same as in C showing the expression of canonical markers used to define the clusters as scaled values. (F) The differentially expressed genes (Padj < 0.05, Bonferroni-corrected t test) between 3 months after dasatinib and diagnosis. The x axis denotes the log2FC of average expression across single cells. (G) The abundances of selected T cell flow cytometry populations as absolute numbers (n = 40) following dasatinib treatment. The P values were calculated with the Mann-Whitney test. (H) UMAP projection of CD8+ T cell clusters identified with scRNA-seq (n = 4) in Figure 1B. The superimposed line represents the 2 unsupervised predicted maturation trajectories. (I) The same as in H showing the cell densities at different time points. (J) The position of cells in the dasatinib-induced trajectory 2. The P values were calculated with the Kruskal-Wallis (left) or Mann-Whitney (right) test. (K) The same as in H showing the expression of markers used to define the clusters as scaled values. *P < 0.05; **P < 0.01; ****P < 0.0001. Box-and-whisker plots are defined in the Methods.