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

Maddalena Noviello; Francesco Manfredi; Eliana Ruggiero; Tommaso Perini; Giacomo Oliveira; Filippo Cortesi; Pantaleo De Simone; Cristina Toffalori; Valentina Gambacorta; Raffaella Greco; Jacopo Peccatori; Monica Casucci; Giulia Casorati; Paolo Dellabona; Masahiro Onozawa; Takanori Teshima; Marieke Griffioen; Constantijn J M Halkes; J H F Falkenburg; Friedrich Stölzel; Heidi Altmann; Martin Bornhäuser; Miguel Waterhouse; Robert Zeiser; Jürgen Finke; Nicoletta Cieri; Attilio Bondanza; Luca Vago; Fabio Ciceri; Chiara Bonini

doi:10.1038/s41467-019-08871-1

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

Nat Commun. 2019 Mar 25;10(1):1065. doi: 10.1038/s41467-019-08871-1.

Authors

Maddalena Noviello¹, Francesco Manfredi¹, Eliana Ruggiero¹, Tommaso Perini², Giacomo Oliveira¹, Filippo Cortesi³, Pantaleo De Simone¹, Cristina Toffalori⁴, Valentina Gambacorta⁴, Raffaella Greco², Jacopo Peccatori², Monica Casucci⁵, Giulia Casorati³, Paolo Dellabona³, Masahiro Onozawa⁶, Takanori Teshima⁶, Marieke Griffioen⁷, Constantijn J M Halkes⁷, J H F Falkenburg⁷, Friedrich Stölzel⁸, Heidi Altmann⁸, Martin Bornhäuser⁸, Miguel Waterhouse⁹, Robert Zeiser⁹, Jürgen Finke⁹, Nicoletta Cieri^{1

10}, Attilio Bondanza⁵, Luca Vago⁴, Fabio Ciceri^{2

11}, Chiara Bonini^{12

13}

Affiliations

¹ IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy.
² IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit, via Olgettina 60, Milan, 20132, Italy.
³ IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit, via Olgettina 60, Milan, 20132, Italy.
⁴ IRCCS San Raffaele Scientifc Institute, Division of Immunology, Transplantation and Infectious Disease, Unit of Immunogenetics, Leukemia Genomics and Immunobiology, via Olgettina 60, Milan, 20132, Italy.
⁵ IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Innovative Immunotherapies Unit, via Olgettina 60, Milan, 20132, Italy.
⁶ Hokkaido University Faculty of Medicine, Graduate School of Medicine, Department of Hematology, 5 Chome Kita 8 Jonishi, Kita, Sapporo, 060-0808, Japan.
⁷ Leiden University Medical Center (LUMC), Department of Hematology, Albinusdreef 2, Leiden, 2333, The Netherlands.
⁸ Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Fetsherstrasse 74, Dresden, 01307, Germany.
⁹ University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation, Hugstetterstr 55, Freiburg, 79106, Germany.
¹⁰ University of Milan, via Festa del Perdono 7, Milan, 20122, Italy.
¹¹ Università Vita-Salute San Raffaele, via Olgettina 60, Milan, 20132, Italy.
¹² IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. [email protected].
¹³ Università Vita-Salute San Raffaele, via Olgettina 60, Milan, 20132, Italy. [email protected].

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 (T_SCM) 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-T_SCM 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antigens, CD / genetics
Antigens, CD / immunology
Antineoplastic Agents / therapeutic use
Bone Marrow Cells / immunology
Bone Marrow Cells / pathology
CTLA-4 Antigen / genetics
CTLA-4 Antigen / immunology
Clonal Anergy*
Female
Gene Expression Regulation, Leukemic*
Glucocorticoid-Induced TNFR-Related Protein / genetics
Glucocorticoid-Induced TNFR-Related Protein / immunology
Hematopoietic Stem Cell Transplantation*
Hepatitis A Virus Cellular Receptor 2 / genetics
Hepatitis A Virus Cellular Receptor 2 / immunology
Humans
Immunologic Memory / genetics*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / immunology*
Leukemia, Myeloid, Acute / pathology
Leukemia, Myeloid, Acute / therapy
Lymphocyte Activation Gene 3 Protein
Male
Middle Aged
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Receptors, KIR / genetics
Receptors, KIR / immunology
Recurrence
Remission Induction
Retrospective Studies
Signal Transduction
Signaling Lymphocytic Activation Molecule Family / genetics
Signaling Lymphocytic Activation Molecule Family / immunology
T-Lymphocytes / immunology*
T-Lymphocytes / pathology
Transplantation, Homologous

Substances

Antigens, CD
Antineoplastic Agents
CD244 protein, human
CTLA-4 Antigen
Glucocorticoid-Induced TNFR-Related Protein
HAVCR2 protein, human
Hepatitis A Virus Cellular Receptor 2
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Receptors, KIR
Signaling Lymphocytic Activation Molecule Family
TNFRSF18 protein, human
Lymphocyte Activation Gene 3 Protein
Lag3 protein, human