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Immune-mediated tumor control in the 5TGM1 transfer model of multiple myeloma

Zoltán Kellermayer, Sabrin Tahri, Madelon M. E. de Jong, Natalie Papazian, Cathelijne Fokkema, Remco Hoogenboezem, Mathijs A. Sanders, Louis Boon, Chelsea Den Hollander, Annemiek Broijl, Pieter Sonneveld, Tom Cupedo
doi: https://doi.org/10.1101/2023.01.18.524505
Zoltán Kellermayer
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Sabrin Tahri
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Madelon M. E. de Jong
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Natalie Papazian
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Cathelijne Fokkema
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Remco Hoogenboezem
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Mathijs A. Sanders
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Louis Boon
2JJP Biologics, Warsaw, Poland
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Chelsea Den Hollander
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Annemiek Broijl
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Pieter Sonneveld
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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Tom Cupedo
1Department of Hematology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands
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  • For correspondence: t.cupedo@erasmusmc.nl
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Abstract

Multiple myeloma is a disease of malignant plasma cells residing in the bone marrow, where interactions with local immune cells are thought to contribute to disease pathobiology. However, since a multiple myeloma diagnosis is virtually always preceded by an asymptomatic precursor phase, identifying early alterations in the bone marrow micro-environment following occupation by multiple myeloma cells remains challenging. Here we used the 5TGM1 transfer model of murine myeloma in combination with myeloma-permissive KaLwRij mice and myeloma-resistant C57Bl/6 mice and hypothesized that differential sensitivity to myeloma in these HLA-identical mouse strains has an immunological basis and might allow for dissection of early immune responses to myeloma cells.

Using flow cytometry and single-cell RNA sequencing we show that C57Bl/6 mice can restrain tumor growth for prolonged periods, associated with activation of cytotoxic immune responses that were absent from KaLwRij mice. Transcriptional analysis of immune cells and stromal cells identified a central role for IFN-signaling in tumor containment, and antibody-mediated neutralization of IFNγ increased both incidence and outgrowth of multiple myeloma in C57Bl/6 mice. Together these findings highlight the ability of a fully functional immune system to control multiple myeloma progression in an IFNγ−dependent manner and suggest that transfer of 5TGM1 cells into parental C57Bl/6 mice can serve as a faithful model to track anti-myeloma immune responses in immune competent and genetically modifiable mice.

Competing Interest Statement

Competing interests A.B. consults for BMS/Celgene, Janssen, Amgen and Sanofi. P.S. is on the advisory board for Amgen, BMS/Celgene, Janssen, Seagen and Pfizer and receives research support from Janssen, BMS/Celgene and Karyopharm.

Footnotes

  • Financial Support 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 European Commission is not responsible for any use that may be made of the information it contains.

  • Competing interests A.B. consults for BMS/Celgene, Janssen, Amgen and Sanofi. P.S. is on the advisory board for Amgen, BMS/Celgene, Janssen, Seagen and Pfizer and receives research support from Janssen, BMS/Celgene and Karyopharm.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 20, 2023.
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Immune-mediated tumor control in the 5TGM1 transfer model of multiple myeloma
Zoltán Kellermayer, Sabrin Tahri, Madelon M. E. de Jong, Natalie Papazian, Cathelijne Fokkema, Remco Hoogenboezem, Mathijs A. Sanders, Louis Boon, Chelsea Den Hollander, Annemiek Broijl, Pieter Sonneveld, Tom Cupedo
bioRxiv 2023.01.18.524505; doi: https://doi.org/10.1101/2023.01.18.524505
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Immune-mediated tumor control in the 5TGM1 transfer model of multiple myeloma
Zoltán Kellermayer, Sabrin Tahri, Madelon M. E. de Jong, Natalie Papazian, Cathelijne Fokkema, Remco Hoogenboezem, Mathijs A. Sanders, Louis Boon, Chelsea Den Hollander, Annemiek Broijl, Pieter Sonneveld, Tom Cupedo
bioRxiv 2023.01.18.524505; doi: https://doi.org/10.1101/2023.01.18.524505

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