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Article

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

1
Laboratory of Hematology, GIGA I3, Department of Hematology, University of Liège, 4000 Liège, Belgium
2
Section for Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Schleswig-Holstein University Medical Center, 24105 Kiel, Germany
3
INSERM, CRCINA, University of Nantes, 44000 Nantes, France
4
Department of Hematology, CHU de Liège, 4000 Liège, Belgium
*
Author to whom correspondence should be addressed.
Academic Editor: Aldo M. Roccaro
Cancers 2021, 13(12), 3072; https://doi.org/10.3390/cancers13123072
Received: 1 April 2021 / Revised: 8 June 2021 / Accepted: 14 June 2021 / Published: 20 June 2021
(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)
We tracked the cytotoxic potential of NK cells towards multiple myeloma cells in daratumumab-mediated antibody-dependent cellular cytotoxicity assays. These cytotoxicity levels could be directly correlated to the expression of the target antigen (CD38) and to the percentage of fratricide between effector cells. Increasing the expression of CD38 on target cells or neutralizing CD38 on effector cells changed the equilibrium between target and effector cell lysis and promoted multiple myeloma cell death. This study highlights the importance of a balanced CD38 expression on target and effector cells and attempts to alter this balance will affect the susceptibility of MM cells towards daratumumab-mediated cellular toxicity.
Multiple myeloma (MM) is an incurable cancer characterized by the proliferation and accumulation of monoclonal plasma cells in the bone marrow. The monoclonal anti-CD38 daratumumab has taken a central place in the different treatment regimens for newly diagnosed and relapsed, refractory myeloma. In this study, we correlated the NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and potential fratricide induced by daratumumab with CD38-expression levels on both effector and target cells. We show that CD38 expression can be modulated by adding all-trans retinoic acid (ATRA) or interferon-α to MM cells to further fine-tune these effects. In addition, we observed that ADCC becomes inefficient when fratricide occurs and both ADCC and fratricide depend on the balance between CD38 expression on effector and target cells. However, the addition of adjuvants (retinoic acid or interferon-α) to myeloma cells or the inhibition of fratricide using a CD38-blocking nanobody on NK-cells can reverse this balance towards ADCC and thus promote lysis of target cells by ADCC. ATRA and interferon-α increased the CD38 expression at the surface of MM cells about three-fold and two-fold, respectively. This increase was of interest for MM cells with low CD38 expression, that became susceptible to daratumumab-mediated ADCC after preincubation. A CD38-blocking nanobody prevented the binding of daratumumab to these NK-cells and blunted the fratricidal effect on effector NK cells. In conclusion, our study highlights the importance of a balanced CD38 expression on target and effector cells and attempts to alter this balance will affect the susceptibility of MM cells towards daratumumab-mediated ADCC. View Full-Text
Keywords: ADCC; CD38; NK-92 cells; multiple myeloma; cellular cytotoxicity assays ADCC; CD38; NK-92 cells; multiple myeloma; cellular cytotoxicity assays
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MDPI and ACS Style

Lejeune, M.; Duray, E.; Peipp, M.; Clémenceau, B.; Baron, F.; Beguin, Y.; Caers, J. Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma. Cancers 2021, 13, 3072. https://doi.org/10.3390/cancers13123072

AMA Style

Lejeune M, Duray E, Peipp M, Clémenceau B, Baron F, Beguin Y, Caers J. Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma. Cancers. 2021; 13(12):3072. https://doi.org/10.3390/cancers13123072

Chicago/Turabian Style

Lejeune, Margaux, Elodie Duray, Matthias Peipp, Béatrice Clémenceau, Frédéric Baron, Yves Beguin, and Jo Caers. 2021. "Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma" Cancers 13, no. 12: 3072. https://doi.org/10.3390/cancers13123072

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