The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape

Madelon M.E. de Jong, Zoltán Kellermayer, Natalie Papazian, Sabrin Tahri, Davine Hofste op Bruinink, Remco Hoogenboezem, Mathijs A. Sanders, Pieter C. van de Woestijne, P. Koen Bos, Cyrus Khandanpour, Jessica Vermeulen, Philippe Moreau, Mark van Duin, Annemiek Broijl, Pieter Sonneveld*, Tom Cupedo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)

Abstract

Progression and persistence of malignancies are influenced by the local tumor microenvironment, and future eradication of currently incurable tumors will, in part, hinge on our understanding of malignant cell biology in the context of their nourishing surroundings. Here, we generated paired single-cell transcriptomic datasets of tumor cells and the bone marrow immune and stromal microenvironment in multiple myeloma. These analyses identified myeloma-specific inflammatory mesenchymal stromal cells, which spatially colocalized with tumor cells and immune cells and transcribed genes involved in tumor survival and immune modulation. Inflammatory stromal cell signatures were driven by stimulation with proinflammatory cytokines, and analyses of immune cell subsets suggested interferon-responsive effector T cell and CD8+ stem cell memory T cell populations as potential sources of stromal cell–activating cytokines. Tracking stromal inflammation in individuals over time revealed that successful antitumor induction therapy is unable to revert bone marrow inflammation, predicting a role for mesenchymal stromal cells in disease persistence.

Original languageEnglish
Pages (from-to)769-780
Number of pages12
JournalNature Immunology
Volume22
Issue number6
Early online date20 May 2021
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
We thank members of Myeloma Research Rotterdam and the Department of Hematology for critical discussions and reading of the manuscript, and the participants, families and nurses for their contributions to this study. We thank N. Leimkühler (Department of Hematology, Erasmus MC, the Netherlands) for help with the collection of healthy bone marrow biopsies and E. Bindels (Department of Hematology, Erasmus MC, the Netherlands) for help with sequencing. This work was supported by grants from the European Myeloma Network (EMN, grant HO95-EMN02-FB01102018 to P.S.) and ZonMw (grant 95103008 to P.S.). C.K. is supported by the Jose Carreras Leukaemia Foundation (grant DJCLS 17R/2018), the Deutsche Krebshilfe (grant 70112392), Deutsche Forschungsgemeinschaft (grant KH331/2–3) and the intramural funding of the faculty of Medicine at University Hospital of Muenster (grant Kha2/002/20). This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 707404 (to Z.K.). The opinions expressed in this document reflect only the authors’ views. The European Commission is not responsible for any use that may be made of the information it contains.

Publisher Copyright:
© 2021, Springer Nature America, Inc.

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