Microvesicles released from multiple myeloma cells are equipped with ectoenzymes belonging to canonical and non-canonical adenosinergic pathways and produce adenosine from ATP and NAD

Oncoimmunology. 2018 May 7;7(8):e1458809. doi: 10.1080/2162402X.2018.1458809. eCollection 2018.

Abstract

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles.

Keywords: Multiple myeloma; adenosine; ectoenzymes; extracellular vesicles; immunosuppression.

Grant support

This work has been supported by A.I.R.C. IG 17273 to V. Pistoia and IG 16985 to M. Massaia, and grant from Compagnia San Paolo to V. Pistoia, F. Malavasi and N. Giuliani. F. Morandi was the recipient of a Fellowship from Fondazione Umberto Veronesi. B. Castella is supported by an AACR – Takeda Fellowship in multiple myeloma. M. Bolzoni and D. Toscani were supported by Fellowships from the Fondazione Italiana per la Ricerca sul Cancro (id. 18152 and 16462, respectively). A.C. Faini is a student of the MD/PhD Program of the University of Torino, Italy.