Analysis of bone marrow-infiltrating T cells from AML patients who relapsed or experienced CR ~1 year after hematopoietic stem cell transplantation (HSCT) showed elevated Tregs in relapsed patients. In HLA-matched (but not HLA-haploidentical) HSCT setting, a higher fraction of CD8+ T cells, including early-differentiation central memory and memory stem cells (TSCM), expressed multiple exhaustion markers, showed reversible functional impairment, and were enriched in tumor-specific T cells in relapsed vs. CR patients. Presence of exhausted TSCM as well as exhaustion markers on HLA-DR-CD8+ T cells ~3.5 months after HSCT was associated with risk of relapse.
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.
Author Info: (1) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy.
Author Info: (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, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. (3) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. (4) IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit, via Olgettina 60, Milan, 20132, Italy. (5) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. (6) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit, via Olgettina 60, Milan, 20132, Italy. (7) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. (8) 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. (9) 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. (10) IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit, via Olgettina 60, Milan, 20132, Italy. (11) IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit, via Olgettina 60, Milan, 20132, Italy. (12) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Innovative Immunotherapies Unit, via Olgettina 60, Milan, 20132, Italy. (13) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit, via Olgettina 60, Milan, 20132, Italy. (14) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Experimental Immunology Unit, via Olgettina 60, Milan, 20132, Italy. (15) Hokkaido University Faculty of Medicine, Graduate School of Medicine, Department of Hematology, 5 Chome Kita 8 Jonishi, Kita, Sapporo, 060-0808, Japan. (16) Hokkaido University Faculty of Medicine, Graduate School of Medicine, Department of Hematology, 5 Chome Kita 8 Jonishi, Kita, Sapporo, 060-0808, Japan. (17) Leiden University Medical Center (LUMC), Department of Hematology, Albinusdreef 2, Leiden, 2333, The Netherlands. (18) Leiden University Medical Center (LUMC), Department of Hematology, Albinusdreef 2, Leiden, 2333, The Netherlands. (19) Leiden University Medical Center (LUMC), Department of Hematology, Albinusdreef 2, Leiden, 2333, The Netherlands. (20) Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Fetsherstrasse 74, Dresden, 01307, Germany. (21) Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Fetsherstrasse 74, Dresden, 01307, Germany. (22) Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Fetsherstrasse 74, Dresden, 01307, Germany. (23) University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation, Hugstetterstr 55, Freiburg, 79106, Germany. (24) University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation, Hugstetterstr 55, Freiburg, 79106, Germany. (25) University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation, Hugstetterstr 55, Freiburg, 79106, Germany. (26) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. University of Milan, via Festa del Perdono 7, Milan, 20122, Italy. (27) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation and Infectious Diseases, Innovative Immunotherapies Unit, via Olgettina 60, Milan, 20132, Italy. (28) 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. (29) IRCCS San Raffaele Scientific Institute, Hematology and Hematopoietic Stem Cell Transplantation Unit, via Olgettina 60, Milan, 20132, Italy. Universita Vita-Salute San Raffaele, via Olgettina 60, Milan, 20132, Italy. (30) IRCCS San Raffaele Scientific Institute, Division of Immunology, Transplantation, and Infectious Diseases, Experimental Hematology Unit, via Olgettina 60, Milan, 20132, Italy. bonini.chiara@hsr.it. Universita Vita-Salute San Raffaele, via Olgettina 60, Milan, 20132, Italy. bonini.chiara@hsr.it.
