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Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT

Author

Listed:
  • Maddalena Noviello

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit)

  • Francesco Manfredi

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit)

  • Eliana Ruggiero

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit)

  • Tommaso Perini

    (IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit)

  • Giacomo Oliveira

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit)

  • Filippo Cortesi

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit)

  • Pantaleo Simone

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit)

  • Cristina Toffalori

    (IRCCS San Raffaele Scientifc Institute, Division of Immunology, Transplantation and Infectious Disease, Unit of Immunogenetics, Leukemia Genomics and Immunobiology)

  • Valentina Gambacorta

    (IRCCS San Raffaele Scientifc Institute, Division of Immunology, Transplantation and Infectious Disease, Unit of Immunogenetics, Leukemia Genomics and Immunobiology)

  • Raffaella Greco

    (IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit)

  • Jacopo Peccatori

    (IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit)

  • Monica Casucci

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Innovative Immunotherapies Unit)

  • Giulia Casorati

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit)

  • Paolo Dellabona

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit)

  • Masahiro Onozawa

    (Hokkaido University Faculty of Medicine, Graduate School of Medicine, Department of Hematology)

  • Takanori Teshima

    (Hokkaido University Faculty of Medicine, Graduate School of Medicine, Department of Hematology)

  • Marieke Griffioen

    (Leiden University Medical Center (LUMC), Department of Hematology)

  • Constantijn J. M. Halkes

    (Leiden University Medical Center (LUMC), Department of Hematology)

  • J. H. F. Falkenburg

    (Leiden University Medical Center (LUMC), Department of Hematology)

  • Friedrich Stölzel

    (University Hospital Carl Gustav Carus Dresden, Technical University Dresden)

  • Heidi Altmann

    (University Hospital Carl Gustav Carus Dresden, Technical University Dresden)

  • Martin Bornhäuser

    (University Hospital Carl Gustav Carus Dresden, Technical University Dresden)

  • Miguel Waterhouse

    (University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation)

  • Robert Zeiser

    (University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation)

  • Jürgen Finke

    (University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation)

  • Nicoletta Cieri

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit
    University of Milan)

  • Attilio Bondanza

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Innovative Immunotherapies Unit)

  • Luca Vago

    (IRCCS San Raffaele Scientifc Institute, Division of Immunology, Transplantation and Infectious Disease, Unit of Immunogenetics, Leukemia Genomics and Immunobiology)

  • Fabio Ciceri

    (IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit
    Università Vita-Salute San Raffaele)

  • Chiara Bonini

    (IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit
    Università Vita-Salute San Raffaele)

Abstract

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet−) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.

Suggested Citation

  • Maddalena Noviello & Francesco Manfredi & Eliana Ruggiero & Tommaso Perini & Giacomo Oliveira & Filippo Cortesi & Pantaleo Simone & Cristina Toffalori & Valentina Gambacorta & Raffaella Greco & Jacopo, 2019. "Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08871-1
    DOI: 10.1038/s41467-019-08871-1
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    Cited by:

    1. Shiyu Zuo & Chuo Li & Xiaolei Sun & Biping Deng & Yibing Zhang & Yajing Han & Zhuojun Ling & Jinlong Xu & Jiajia Duan & Zelin Wang & Xinjian Yu & Qinlong Zheng & Xiuwen Xu & Jiao Zong & Zhenglong Tian, 2024. "C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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