Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

Jani Huuhtanen, Dipabarna Bhattacharya, Tapio Lönnberg, Matti Kankainen, Cassandra Kerr, Jason Theodoropoulos, Hanna Rajala, Carmelo Gurnari, Tiina Kasanen, Till Braun, Antonella Teramo, Renato Zambello, Marco Herling, Fumihiro Ishida, Toru Kawakami, Marko Salmi, Thomas Loughran, Jaroslaw P. Maciejewski, Harri Lähdesmäki, Tiina Kelkka and Satu Mustjoki ()
Additional contact information
Jani Huuhtanen: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Dipabarna Bhattacharya: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Tapio Lönnberg: University of Turku and Åbo Akademi University
Matti Kankainen: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Cassandra Kerr: Cleveland Clinic
Jason Theodoropoulos: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Hanna Rajala: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Carmelo Gurnari: Cleveland Clinic
Tiina Kasanen: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Till Braun: University of Cologne (UoC)
Antonella Teramo: Padova University School of Medicine
Renato Zambello: Padova University School of Medicine
Marco Herling: University of Cologne (UoC)
Fumihiro Ishida: Shinshu University School of Medicine
Toru Kawakami: Shinshu University School of Medicine
Marko Salmi: University of Turku
Thomas Loughran: University of Virginia
Jaroslaw P. Maciejewski: Cleveland Clinic
Harri Lähdesmäki: Aalto University
Tiina Kelkka: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Satu Mustjoki: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract T cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded T cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as a chronic T cell response to an antigen, the function of the non-leukemic immune system in this response is largely uncharacterized. Here, by utilizing single-cell RNA and T cell receptor profiling (scRNA+TCRαβ-seq), we show that irrespective of STAT3 mutation status, T-LGLL clonotypes are more cytotoxic and exhausted than healthy reactive clonotypes. In addition, T-LGLL clonotypes show more active cell communication than reactive clones with non-leukemic immune cells via costimulatory cell–cell interactions, monocyte-secreted proinflammatory cytokines, and T-LGLL-clone-secreted IFNγ. Besides the leukemic repertoire, the non-leukemic T cell repertoire in T-LGLL is also more mature, cytotoxic, and clonally restricted than in other cancers and autoimmune disorders. Finally, 72% of the leukemic T-LGLL clonotypes share T cell receptor similarities with their non-leukemic repertoire, linking the leukemic and non-leukemic repertoires together via possible common target antigens. Our results provide a rationale to prioritize therapies that target the entire immune repertoire and not only the T-LGLL clonotype.

Date: 2022
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DOI: 10.1038/s41467-022-29173-z

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