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

Huuhtanen, Jani ; Adnan-Awad, Shady ; Theodoropoulos, Jason ; Forstén, Sofia ; Warfvinge, Rebecca LU ; Dufva, Olli ; Bouhlal, Jonas ; Dhapola, Parashar LU ; Duàn, Hanna and Laajala, Essi , et al. (2023) In Leukemia
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... (More)

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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type
Contribution to journal
publication status
epub
subject
in
Leukemia
publisher
Nature Publishing Group
external identifiers
  • pmid:37919606
  • scopus:85175531977
ISSN
0887-6924
DOI
10.1038/s41375-023-02074-w
language
English
LU publication?
yes
id
fe9b88c9-9079-4e24-99b2-1c2e96671517
date added to LUP
2023-12-06 12:25:24
date last changed
2024-04-19 07:57:20
@article{fe9b88c9-9079-4e24-99b2-1c2e96671517,
  abstract     = {{<p>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 CD56<sup>dim</sup> 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 + T<sub>EMRA</sub> 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.</p>}},
  author       = {{Huuhtanen, Jani and Adnan-Awad, Shady and Theodoropoulos, Jason and Forstén, Sofia and Warfvinge, Rebecca and Dufva, Olli and Bouhlal, Jonas and Dhapola, Parashar and Duàn, Hanna and Laajala, Essi and Kasanen, Tiina and Klievink, Jay and Ilander, Mette and Jaatinen, Taina and Olsson-Strömberg, Ulla and Hjorth-Hansen, Henrik and Burchert, Andreas and Karlsson, Göran and Kreutzman, Anna and Lähdesmäki, Harri and Mustjoki, Satu}},
  issn         = {{0887-6924}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Leukemia}},
  title        = {{Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation}},
  url          = {{http://dx.doi.org/10.1038/s41375-023-02074-w}},
  doi          = {{10.1038/s41375-023-02074-w}},
  year         = {{2023}},
}