A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia
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<sup>+</sup> 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
- Jacqueline Suen Garcia (ORCID: https://orcid.org/0000-0003-2118-6302)
- Joost B. Koedijk (ORCID: https://orcid.org/0000-0001-6463-3307)
- Marta Fiocco (ORCID: https://orcid.org/0000-0001-5588-0277)
- Kristina Bang Christensen (ORCID: https://orcid.org/0000-0002-0008-7359)
- Marijn A. Vermeulen (ORCID: https://orcid.org/0000-0001-8926-1140)
- Rubina Moeniralam
- C. Michel Zwaan (ORCID: https://orcid.org/0000-0001-6892-8268)
- Inge van der Werf (ORCID: https://orcid.org/0000-0002-8159-399X)
- Alicia Perzolli (ORCID: https://orcid.org/0000-0003-1302-0943)
- Thanasis Margaritis (ORCID: https://orcid.org/0000-0003-4040-2015)
- Livius Penter (ORCID: https://orcid.org/0000-0002-9060-0207)
- Hester A. de Groot‐Kruseman (ORCID: https://orcid.org/0000-0001-7038-188X)
- Catherine J. Wu (ORCID: https://orcid.org/0000-0002-3348-5054)
- Olaf T Heidenreich (ORCID: https://orcid.org/0000-0001-5404-6483)
- Dennis S. Metselaar (ORCID: https://orcid.org/0000-0001-5559-2435)
- Joyce I. Meesters-Ensing (ORCID: https://orcid.org/0000-0003-0780-9227)
- Scott J. Rodig (ORCID: https://orcid.org/0000-0003-1761-9769)
- Henrik Hasle (ORCID: https://orcid.org/0000-0003-3976-9231)
- Kathleen L. Pfaff (ORCID: https://orcid.org/0000-0003-3311-5384)
- Farnaz Barneh (ORCID: https://orcid.org/0000-0003-4715-9732)
- Stefan Nierkens (ORCID: https://orcid.org/0000-0003-3406-817X)
- Mirjam E. Belderbos (ORCID: https://orcid.org/0000-0002-6164-2918)
- Billie Porter
Institutions
- Broad Institute (US)
- Leiden University (NL)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- German Cancer Research Center (DE)
- California Institute for Regenerative Medicine (US)
- Heidelberg University (DE)
- Leiden University Medical Center (NL)
- Aarhus University Hospital (DK)
- University Medical Center Utrecht (NL)
- Humboldt-Universität zu Berlin (DE)
- Sanford Consortium for Regenerative Medicine (US)
- Vivantes Klinikum (DE)
- Oncode Institute (NL)
- Hopp Children's Cancer Center Heidelberg (DE)
- Dana-Farber Cancer Institute (US)
- Princess Máxima Center (NL)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Erasmus MC - Sophia Children’s Hospital (NL)
- Massachusetts Institute of Technology (US)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Newcastle University (GB)
Publication Details
- Journal
- Leukemia
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1038/s41375-024-02381-w
- Citations
- 11
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 2.65
Funders
- Conquer Cancer Foundation
- American Society of Hematology
- Bristol-Myers Squibb
- Leukemia and Lymphoma Society
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- Deutsche Krebshilfe
- Stichting Kinderen Kankervrij
- Berlin Institute of Health
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute
- Center for Scientific Review