Abstract
Ectoenzymes are cell surface molecules, which represent functional bridges between the environment and the cytoplasm. One set of ectoenzymes—CD39, CD38, CD203a, and CD73—leads to the generation of adenosine (ADO) by metabolizing ATP and NAD+. While ADO is known to control inflammation and suppress immune responses, other aspects of ADO function are still obscure, mainly due to its short half-life in biological fluids. Human multiple myeloma (MM) grows in the closed system of the bone marrow (BM) niche representing an ideal setting for studying ectoenzymes and their products. Another source of information on ectoenzyme function may derive from in vivo results of anti-CD38 antibody therapy in MM. Current results, obtained from in vitro models and from preliminary in vivo findings, indicate that ectoenzymes produce ADO locally in the BM niche. Furthermore, MM cells release microvesicles (MV), which thanks to their molecular cargo and surface ectoenzymes may function as particulate communicators outside of the niche. During anti-CD38 antibody therapy, the MV carry therapeutic IgG, determining that the prevalent orientation of MV will be toward cells and tissues expressing receptors for the IgG Fc domain. The resulting picture is one where MM adopts an immune escape strategy based on reshaping the environmental niche. This adaptation is followed by actions of MV that are exerted in biological fluids and circulating immune cells. By coating FcRs+ cells, MV modify pericellular spaces, reproducing the metabolic halo generated by ectoenzymes within closed systems.
Highlights
The present perspective aims to highlight the contribution of adenosinergic ectoenzymes to the metabolic pathways that contribute to tumor growth and active immune evasion
It is generally accepted that MM exploits the capacity of pH to modify the environment and the immune response within the context of the niche. This is confirmed by the observation that low pH in bone marrow (BM) plasma is paralleled by (i) phenotypic modifications of the cells surrounding the tumor and (ii) by increased levels of locally produced ADO
An improvement may come when ADO is produced in the context of a tissue or closed system, which facilitates the interaction among biological fluids and cells
Summary
The present perspective aims to highlight the contribution of adenosinergic ectoenzymes to the metabolic pathways that contribute to tumor growth and active immune evasion. It is generally accepted that MM exploits the capacity of pH to modify the environment and the immune response within the context of the niche This is confirmed by the observation that low pH in BM plasma is paralleled by (i) phenotypic modifications of the cells surrounding the tumor and (ii) by increased levels of locally produced ADO. Extracellular NAD+ is metabolized by CD38, CD203a, and CD73, confirming observations obtained in vitro in a human T leukemia line [7] and in vivo in human NK cells [25] These ectonucleotidases operate in a discontinuous fashion (meaning that the components of the pathway do not need to be expressed by the same cell), but the metabolic halo around the cells forms a transmission chain of reaction products. It remains to be seen whether the observations seen in the niche may hold true outside of a closed environment
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