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Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies
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CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by
Federica Costa1, Benedetta Dalla Palma1,2, Nicola Giuliani1,2
1Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
Abstract:
In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs.
Insights
CD38, a target in multiple myeloma (MM), is an ectoenzyme producing adenosine. Drugs can increase CD38 expression, enhancing anti-CD38 antibody efficacy in MM treatment.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- CD38 is a glycoprotein in the bone marrow microenvironment, highly expressed on multiple myeloma (MM) cells.
- CD38 functions as an ectoenzyme, converting NAD+ to adenosine, an immunosuppressive factor.
- CD38 is a target for monoclonal antibody (mAb) therapies in MM.
Purpose of the Study:
- To explore the role of CD38 in MM pathogenesis and its potential as a therapeutic target.
- To investigate the relationship between CD38 expression and the efficacy of anti-CD38 mAbs.
- To evaluate the impact of certain drugs on CD38 expression and their potential synergistic effects with anti-CD38 mAbs.
Main Methods:
- Review of literature on CD38 function, expression in MM, and anti-CD38 therapies.
- Analysis of the ectoenzyme activity of CD38 and its role in adenosine production.
- Investigation of drug-induced modulation of CD38 expression.
Main Results:
- High CD38 surface density on MM cells drives the development of anti-CD38 mAbs.
- The efficacy of anti-CD38 mAbs is dependent on CD38 expression on MM and immune cells.
- Certain drugs (lenalidomide, panobinostat, ATRA, DNMT inhibitors) can increase CD38 expression.
Conclusions:
- Modulating CD38 expression by increasing its density on MM cells is crucial for potentiating anti-CD38 mAb efficacy.
- Combining anti-CD38 mAbs with drugs that upregulate CD38 presents a promising strategy for MM clinical trials.
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