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

• Main Authors: Bhattacharya, D. (Author), Braun, T. (Author), Gurnari, C. (Author), Herling, M. (Author), Huuhtanen, J. (Author), Ishida, F. (Author), Kankainen, M. (Author), Kasanen, T. (Author), Kawakami, T. (Author), Kelkka, T. (Author), Kerr, C. (Author), Lähdesmäki, H. (Author), Lönnberg, T. (Author), Loughran, T. (Author), Maciejewski, J.P (Author), Mustjoki, S. (Author), Rajala, H. (Author), Salmi, M. (Author), Teramo, A. (Author), Theodoropoulos, J. (Author), Zambello, R. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Subjects: CD8+ T lymphocyte; CD8-Positive T-Lymphocytes; genetics; human; Humans; large granular lymphocyte leukemia; Leukemia, Large Granular Lymphocytic; lymphocyte antigen receptor; mutation; Mutation; Receptors, Antigen, T-Cell; T lymphocyte; T-Lymphocytes
• Online Access: View Fulltext in Publisher
• ISBN: 20411723 (ISSN)
• DOI: 10.1038/s41467-022-29173-z

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. © 2022, The Author(s).