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Multiple myeloma gammopathies

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Leukemia volume 35, pages 189–200 (2021)Cite this article

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Abstract

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T-cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

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Fig. 1: CD38+ NK cells are essential for Dara-induced killing of MM cells.
Fig. 2: Dara induces direct CD38+ NK cell activation.
Fig. 3: Dara induces CD38 protein reduction in NK cells and Ca2+ mobilization.
Fig. 4: NK cell activation by Dara is essential for monocyte activation and polarization.
Fig. 5: Dara-resistant patients retain surface CD38 on MM cells.
Fig. 6: Proposed mechanism of action.

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Acknowledgements

We thank Dori Triplett, Evelyn Flores, Elizabeth Hartman, and Debbie Flood for administrative support. Research was in part supported by the National Institutes of Health under grant number NIH-2-R01-CA201382 (FP and CCH), in part under NIH-2-R01-CA238429-01 (FP, JS, and XW) and in part by the Steven Gordon and Briskin Family Innovation Grant. We also thank Suzan King and Steve Allen for their support. Research reported in this publication included work performed at the Liquid Tissue Bank, Analytical Cytometry, and Integrative Genomics and Bioinformatics shared resource cores supported by the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. These authors contributed equally: Domenico Viola, Ada Dona

Authors and Affiliations

  1. Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 91010, USA

    Domenico Viola, Ada Dona, Enrico Caserta, Estelle Troadec, Francesca Besi, Emine Gulsen Gunes, James F. Sanchez, Jihane Khalife, Marianna Martella, Chatchada Karanes, Myo Htut, Xiuli Wang, Michael Rosenzweig, Arnab Chowdhury, Stephen J. Forman, Steven T. Rosen, Amrita Krishnan & Flavia Pichiorri

  2. Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA

    Domenico Viola, Ada Dona, Enrico Caserta, Estelle Troadec, Francesca Besi, Lucy Ghoda, Emine Gulsen Gunes, Jihane Khalife, Marianna Martella, Guido Marcucci & Flavia Pichiorri

  3. Hematopoietic Tissue Repository Shared Resource, City of Hope, Duarte, CA, 91010, USA

    Tinisha McDonald

  4. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Douglas Sborov

  5. Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA

    Rodney R. Miles

  6. Department of Molecular Imaging & Therapy, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA

    Paul J. Yazaki, Todd Ebner & John Shively

  7. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Craig C. Hofmeister

  8. Translational Genomics Research Institute, Phoenix, AZ, 85004, USA

    Jonathan J. Keats

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Contributions

DV, AD, SJF, PJY, JJK, JS, STR, CCH, GM, AK, and FP designed research; DV, AD, MM, EGG, ET, EC, FB, XW, JK, TM, STR, CK, MH, MR, DS, RRM, and TE performed research; DV, AC, LG, JFS, and XW analyzed data; AD, JFS, AK, and FP wrote the manuscript; all authors reviewed the manuscript.

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Correspondence to Amrita Krishnan or Flavia Pichiorri.

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AK is a consultant for Celgene and Janssen, serves on the speakers’ bureau for SutroBioPharma, zPredicta, Celgene, Amgen, and Takeda, and has stock ownership in Celgene. CCH has received research grants from Takeda & Oncolytics Biotech; research and personal grants from Janssen, BMS, Sanofi, Nektar, and Karyopharm; and personal grants from Imbrium Pharmaceuticals and Oncopeptides, all outside the submitted work.

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Viola, D., Dona, A., Caserta, E. et al. Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting. Leukemia 35, 189–200 (2021). https://doi.org/10.1038/s41375-020-0810-4

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