A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia
Leukemia, vol. 38, pp. 2332–2343
Abstract
Abstract Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+ T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.
Authors 23
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Princess Máxima Center · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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University of California San Diego · Oncode Institute · Princess Máxima Center
Affiliation as printed
Oncode Institute, 3521 AL, Utrecht, The Netherlands
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
Sanford Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Broad Institute · Harvard University · German Cancer Research Center · Humboldt-Universität zu Berlin · Dana-Farber Cancer Institute · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Deutsches Konsortium für Translationale Krebsforschung · Massachusetts Institute of Technology · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Hematology, Oncology, and Cancer Immunology, Campus Virchow Klinikum, Berlin, Germany
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany
Harvard Medical School, Boston, MA, USA
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Princess Máxima Center · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Princess Máxima Center · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Leiden University · Leiden University Medical Center · Princess Máxima Center
Affiliation as printed
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
Mathematical Institute, Leiden University, Leiden, The Netherlands
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
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Affiliation as printed
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Affiliation as printed
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Harvard University · Dana-Farber Cancer Institute
Affiliation as printed
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
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Affiliation as printed
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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Broad Institute · Brigham and Women's Hospital · Harvard University · Dana-Farber Cancer Institute · Massachusetts Institute of Technology
Affiliation as printed
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
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Affiliation as printed
Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
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University Medical Center Utrecht · Princess Máxima Center
Affiliation as printed
Center for Translational Immunology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Princess Máxima Center · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
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Olaf T Heidenreich corresponding
University Medical Center Utrecht · Princess Máxima Center · Newcastle University
Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands. o.t.heidenreich@prinsesmaximacentrum.nl
University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands. o.t.heidenreich@prinsesmaximacentrum.nl
Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK. o.t.heidenreich@prinsesmaximacentrum.nl
University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
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