Oncotarget

Research Papers:

Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation

Federica Costa, Denise Toscani, Antonella Chillemi, Valeria Quarona, Marina Bolzoni, Valentina Marchica, Rosanna Vescovini, Cristina Mancini, Eugenia Martella, Nicoletta Campanini, Chiara Schifano, Sabrina Bonomini, Fabrizio Accardi, Alberto L. Horenstein, Franco Aversa, Fabio Malavasi and Nicola Giuliani _

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Oncotarget. 2017; 8:56598-56611. https://doi.org/10.18632/oncotarget.17896

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Abstract

Federica Costa1,*, Denise Toscani1,*, Antonella Chillemi2, Valeria Quarona2, Marina Bolzoni1, Valentina Marchica1,6, Rosanna Vescovini3, Cristina Mancini4, Eugenia Martella4, Nicoletta Campanini4, Chiara Schifano5, Sabrina Bonomini5, Fabrizio Accardi1,5, Alberto L. Horenstein2, Franco Aversa1,5, Fabio Malavasi2 and Nicola Giuliani1,5,6

1Department of Medicine and Surgery, University of Parma, Parma, Italy

2Laboratory of Immunogenetics, Department of Medical Sciences and CeRMS, University of Torino, Torino, Italy

3Clinical Medicine Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy

4Pathology, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy

5Hematology and BMT Center, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy

6CoreLab, “Azienda Ospedaliero-Universitaria di Parma”, Parma, Italy

*These authors contributed equally to this work

Correspondence to:

Nicola Giuliani, email: [email protected]

Keywords: multiple myeloma, CD38, osteoclast, bone disease, immunotherapy

Received: October 27, 2016     Accepted: April 29, 2017     Published: May 16, 2017

ABSTRACT

It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies. Results indicate that only plasma cells expressed CD38 at high level within the bone niche. In addition, the flow cytometry analysis shows that CD38 was also expressed by monocytes and early osteoclast progenitors but not by osteoblasts and mature osteoclasts. Indeed, CD38 was lost during in vitro osteoclastogenesis. Consistently, we found that Daratumumab reacted with CD38 expressed on monocytes and its binding inhibited in vitro osteoclastogenesis and bone resorption activity from bone marrow total mononuclear cells of MM patients, targeting early osteoclast progenitors. The inhibitory effect was not observed from purified CD14+ cells, suggesting an indirect inhibitory effect of Daratumumab. Interestingly, all-trans retinoic acid treatment increased the inhibitory effect of Daratumumab on osteoclast formation.

These observations provide a rationale for the use of an anti-CD38 antibody-based approach as treatment for multiple myeloma-induced osteoclastogenesis.


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