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

Abstract

CommentaryThe tumor microenvironment is rich extracellular mono-and dinucleotides (ATP, NAD+), which are metabolized by cell surface ecto enzymes to produce increased local concentrations of adenosine (Ado), a nucleoside involved the control of inflammation and immune responses [1]. A recent study by our group demonstrated that adenosinergic pathways contribute to customize the immune homeostasis of multiple myeloma (MM) [2]. A plasma cell malignancy, MM prevalently develops and expands with bone marrow (BM) niches [3]. 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. At acidic pH, CD38 can also catalyze the exchange of the nicotinamide group of NADP + with nicotinic acid and produce NAADP + and ADPRP.All of the final products are basic regulators of calcium signaling [6]. The initial disassembly of NAD + is followed by adenosinergic activity, provided that CD38 is operating the presence of other ectoenzymes (ectonucleotide pyrophosphatase/phosphodiesterase CD203a and 5'-nucleotidase CD73). These findings point to the existence of an alternative axis for extracellular production of the immunosuppressive Ado. Such a pathway would be able to flank and, some instances, to bypass the canonical pathway based on the conversion of ATP by the ecto-nucleoside triphosphate diphosphohydrolase CD39 [7,8]. These coordinated networks may be hijacked by the tumour for its own purposes.These observations are relevant to myeloma homeostasis the BM. For energy production and the synthesis of nucleotides and other macromolecules, malignant plasma cells favour glycolysis over oxidative phosphorylation (the Warburg effect), thus sacrificing efficiency for speed. 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]. The functional relevance is that these NK cells operate as activated immune effector/regulatory cells inhibiting autologous CD4+ T cell proliferation. This strategy of immune escape has already been observed: melanoma cells produce Ado through a CD38/CD203a/CD73 pathway and suppress CD4+ T ce...