A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia
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
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD Rotterdam, The Netherlands
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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
Oncode Institute, 521 AL, 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
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD Rotterdam, 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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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
Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD Rotterdam, The Netherlands
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Olaf T Heidenreich corresponding
Princess Máxima Center · Newcastle University
Affiliation as printed
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne NE1 RU, UK
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