NAD+-Metabolizing Ectoenzymes in Remodeling Tumor–Host Interactions: The Human Myeloma Model

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD+ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD+, belongs to the ectoenzymatic network generating intracellular Ca2+-active metabolites. Within this general framework, the extracellular conversion of NAD+ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo.

Adenosine in the Bone Marrow Myeloma Niche: Immune Checkpoint and Key Player in the Progression of Myeloma Disease

“…As a consequence, Ado may assume the role of a local hormone, adjusting cellular metabolism either via low or high affinity specific receptors expressed by normal and tumor cells [5]. Evidence for this is our finding that CD56 bright CD16 + NK cells produce Ado through a CD38-mediated pathway [9].…”

“…This metabolic shift is hallmarked by hypoxic conditions, and leads to a decrease ATP concentrations and a concurrent increase NAD+ levels to susta high-rate glycolysis. this context, extracellular Ado may originates and be released from tumor cells depleted of ATP, or it may derive from extracellular ATP and NAD+ leaked from damaged tumor tissues.As a consequence, Ado may assume the role of a local hormone, adjusting cellular metabolism either via low or high affinity specific receptors expressed by normal and tumor cells [5]. Evidence for this is our finding that CD56 bright CD16 + NK cells produce Ado through a CD38-mediated pathway [9].…”

“…Malignant plasma cells at all stages of the disease overexpress CD38 [4], a molecule with widespread tissue distribution and complex functions not yet fully elucidated. CD38 is a 45-kDa type II (or III) trans membrane glycoprote expressed by several immune and nonimmune cell types, and it plays a dual role as a receptor and as an ectoenzyme [5]. As a nucleotide-metabolizing ectoenzyme, CD38 catalyzes at neutral pH the extracellular conversion of a dinucleotide of adenine (NAD + ) to cADPR and ADPR.…”

CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma

“…Furthermore, recent in vitro studies suggest that binding of daratumumab to CD38 may cause redistribution of CD38 molecules, formation of distinct polar aggregates, and subsequent release of tumor microvesicles. 16 Finally, trogocytosis of CD38-daratumumab complexes by Fcg receptor-expressing effector cells and direct internalization may also play a role in loss of CD38. 45 Downregulation of CD38 on MM cells is a transient event, because ;6 months after the last daratumumab infusion, CD38 expression increases again.…”

“…14 It has also been shown that daratumumab modulates the enzymatic activity of CD38, which potentially leads to a reduction in immunosuppressive adenosine levels. 15,16 This shift away from an immunosuppressive environment is hypothesized to result in an improved host-antitumor immune response.…”