Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation

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Volume Title
A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
Date
2024
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Language
en
Pages
109–125
Series
Leukemia, Volume 38
Abstract
Immunological control of residual leukemia cells is thought to occur in patients with chronic myeloid leukemia (CML) that maintain treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation. To study this, we analyzed 55 single-cell RNA and T cell receptor (TCR) sequenced samples (scRNA+TCRαβ-seq) from patients with CML (n = 13, N = 25), other cancers (n = 28), and healthy (n = 7). The high number and active phenotype of natural killer (NK) cells in CML separated them from healthy and other cancers. Most NK cells in CML belonged to the active CD56dim cluster with high expression of GZMA/B, PRF1, CCL3/4, and IFNG, with interactions with leukemic cells via inhibitory LGALS9–TIM3 and PVR–TIGIT interactions. Accordingly, upregulation of LGALS9 was observed in CML target cells and TIM3 in NK cells when co-cultured together. Additionally, we created a classifier to identify TCRs targeting leukemia-associated antigen PR1 and quantified anti-PR1 T cells in 90 CML and 786 healthy TCRβ-sequenced samples. Anti-PR1 T cells were more prevalent in CML, enriched in bone marrow samples, and enriched in the mature, cytotoxic CD8 + TEMRA cluster, especially in a patient maintaining TFR. Our results highlight the role of NK cells and anti-PR1 T cells in anti-leukemic immune responses in CML.
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Funding Information: This work was supported by Nordic Cancer Union, the EUTOS project for CML 2018, Academy of Finland, Finnish special governmental subsidy for health sciences, research and training, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Helsinki Institute of Life Science, Cancer Foundation Finland, and Relander Foundation. JH was supported by Finnish Hematology Association, Blood Disease Research Foundation, Helsinki Institute for Life Science, Biomedicum Helsinki Foundation, Finnish Medical Foundation, K. Albin Johansson Foundation, Kaute Foundation, and Emil Aaltonen Foundation. We further acknowledge the computational resources provided by the Aalto Science-IT project, single-cell sequencing and flow cytometry core facilities (University of Helsinki, Helsinki Institute of Life Sciences, Lund University Center for Translational Genomics and SciLifeLab Clinical Genomics Lund) and all the personnel in the Hematology Research Unit Helsinki for insightful conversations. We are deeply grateful to all patients who participated in the study and generously contributed samples. Publisher Copyright: © 2023, The Author(s).
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Huuhtanen, J, Adnan-Awad, S, Theodoropoulos, J, Forstén, S, Warfvinge, R, Dufva, O, Bouhlal, J, Dhapola, P, Duàn, H, Laajala, E, Kasanen, T, Klievink, J, Ilander, M, Jaatinen, T, Olsson-Strömberg, U, Hjorth-Hansen, H, Burchert, A, Karlsson, G, Kreutzman, A, Lähdesmäki, H & Mustjoki, S 2024, ' Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation ', Leukemia, vol. 38, pp. 109–125 . https://doi.org/10.1038/s41375-023-02074-w