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

• Type of Material: Article
• Authors: Domenico Viola, Judy and Bernard Briskin Center for Multiple Myeloma Research; Ada Dona, Judy and Bernard Briskin Center for Multiple Myeloma Research; Enrico Caserta, Judy and Bernard Briskin Center for Multiple Myeloma Research; Estelle Troadec, Judy and Bernard Briskin Center for Multiple Myeloma Research; Francesca Besi, Judy and Bernard Briskin Center for Multiple Myeloma Research; Tinisha McDonald, Hematopoietic Tissue Repository Shared Resource; Lucy Ghoda, Beckman Research Institute; Emine Gulsen Gunes, Judy and Bernard Briskin Center for Multiple Myeloma Research; James F. Sanchez, Judy and Bernard Briskin Center for Multiple Myeloma Research; Jihane Khalife, Judy and Bernard Briskin Center for Multiple Myeloma Research; Marianne Martella, Judy and Bernard Briskin Center for Multiple Myeloma Research; Chatchada Karanes, Judy and Bernard Briskin Center for Multiple Myeloma Research; Myo Htut, Judy and Bernard Briskin Center for Multiple Myeloma Research; Xiuli Wang, Judy and Bernard Briskin Center for Multiple Myeloma Research; Michael Rosenzweig, Judy and Bernard Briskin Center for Multiple Myeloma Research; Arnab Chowdhury, Judy and Bernard Briskin Center for Multiple Myeloma Research; Douglas Sborov, University of Utah; Rodney R. Miles, University of Utah; Paul J. Yazaki, Beckman Research Institute; Todd Ebner, Beckman Research Institute; Craig Hofmeister, Emory University; Stephen J. Forman, Judy and Bernard Briskin Center for Multiple Myeloma Research; Steven T. Rosen, Judy and Bernard Briskin Center for Multiple Myeloma Research; Guido Marcucci, Beckman Research Institute; John Shively, Beckman Research Institute; Jonathan J. Keats, Translational Genomics Research Institute; Amrita Krishnan, Judy and Bernard Briskin Center for Multiple Myeloma Research; Flavia Pichiorri, Judy and Bernard Briskin Center for Multiple Myeloma Research
• Language: English
• Date: 2020-04-16
• Publisher: SPRINGERNATURE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• Final Published Version (URL): http://dx.doi.org/10.1038/s41375-020-0810-4
• Title of Journal or Parent Work: LEUKEMIA
• Volume: 35
• Issue: 1
• Start Page: 189
• End Page: 200
• Grant/Funding Information: Research was in part supported by the National Institute of Health under grant number NIH-2-R01-CA201382(FP, CCH) and in part under the NIH-2-R01-CA238429-01 (FP, JS, XW) and in part by the Steven Gordon and Briskin Family Innovation Grant. 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.
• Keywords: UP-REGULATION; Life Sciences & Biomedicine; MONOTHERAPY; Oncology; Hematology; Science & Technology; IFN-GAMMA; BORTEZOMIB; LENALIDOMIDE; MULTIPLE; DEXAMETHASONE
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

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.