Analyzing the genome and gene expression profiles of acute myeloid leukemia (AML) samples taken from 40 patients at diagnosis and at relapse after allogeneic hematopoietic cell transplantation, Toffalori et al. found changes that mediate immune escape and prevent donor-derived T cells from recognizing AML. AML blasts downregulated costimulatory ligands and adhesion molecules (e.g. CD11A) and upregulated inhibitory molecules (e.g. PD-L1, B7-H3), while donor T cells upregulated PD-1. AML blasts also downregulated CIITA (regulator of HLA-II transcription) and the expression of HLA-II molecules.
Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
Author Info: (1) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, It
Author Info: (1) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. (2) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. (3) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy. (4) Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy. (5) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. Dana-Farber Cancer Institute, Boston, MA, USA. (6) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy. (7) Genomic and Bioinformatics Unit, Department of Health Sciences, University of Milano, Milano, Italy. (8) Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy. (9) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. (10) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. University of Milano, Milano, Italy. (11) Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. University of Milano, Milano, Italy. (12) Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. (13) Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. (14) Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy. (15) Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy. (16) Translational Stem Cell and Leukemia Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy. (17) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. Translational Stem Cell and Leukemia Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy. (18) Department of Hematology, Oncology and Stem Cell Transplantation, Universitatsklinikum Freiburg, Freiburg, Germany. (19) Department of Hematology, Oncology and Stem Cell Transplantation, Universitatsklinikum Freiburg, Freiburg, Germany. (20) Department of Hematology, Oncology and Stem Cell Transplantation, Universitatsklinikum Freiburg, Freiburg, Germany. (21) Department of Bone Marrow Transplantation, Universitatsklinikum Essen, Essen, Germany. (22) Department of Bone Marrow Transplantation, Universitatsklinikum Essen, Essen, Germany. (23) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (24) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (25) Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan. (26) Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan. (27) Department of Haematology, Institut Paoli Calmettes, Marseille, France. (28) Department of Haematology, Institut Paoli Calmettes, Marseille, France. (29) Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. (30) Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. (31) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. (32) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. (33) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. (34) Genomic and Bioinformatics Unit, Department of Health Sciences, University of Milano, Milano, Italy. (35) Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy. Dana-Farber Cancer Institute, Boston, MA, USA. (36) Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy. (37) Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy. (38) Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy. Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy. (39) Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy. (40) Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. San Raffaele Vita-Salute University, Milano, Italy. (41) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. Institute for Experimental Cellular Therapy, Universitatsklinikum Essen, Essen, Germany. (42) Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. San Raffaele Vita-Salute University, Milano, Italy. (43) Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy. vago.luca@hsr.it. Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milano, Italy. vago.luca@hsr.it.
