Functional insights into nucleotide-metabolizing ectoenzymes expressed by bone marrow-resident cells in patients with multiple myeloma

Horenstein, Alberto L.; Morandi, Fabio; Bracci, Cristiano; Pistoia, Vito; Malavasi, Fabio

doi:10.1016/j.imlet.2018.11.007

Cited by 9 publications

(13 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reports from our group indicate that ADO production within the BM niche of patients with multiple myeloma may contribute to tumor progression. 24,40,41 In line with this, it is reasonable to speculate that the combined adenosinergic activity of ectoenzymes located on infiltrating NB cells and on BM-resident cells lead to an increased ADO production inside BM microenvironment, that may lead to the generation of an impaired local anti-tumor immune response, with a consequent spreading of metastatic NB cells. The inference is that metastatic NB cells sustain themselves the metastatic spread, by increasing expression and function of adenosinergic ectoenzymes by BM-resident cells.…”

Section: Discussionmentioning

confidence: 78%

Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells

et al. 2019

Self Cite

View full text Add to dashboard Cite

Metastatic diffusion of Neuroblastoma (NB) cells in the bone marrow (BM) represents the most negative prognostic factors for NB patients. Multiple immune escape mechanisms are postulated as responsible. Our working hypothesis is that adenosine (ADO), an immunosuppressive molecule along with the ectoenzymatic pathways (CD39-CD73 and CD38-CD203a/PC-1-CD73) controlling its production, are involved in the dynamics of NB cells in the BM. The results indicate that ectonucleotidases are expressed by i) NB cell lines, ii) metastatic NB cells isolated from NB patients' BM, iii) microvesicles (MV) derived from both NB cell types and iv) resident BM cell populations. BM infiltration by NB cells increased CD203a/PC-1 and CD73 expression on lymphoid and myeloid cells, respectively. Expressions of ectoenzymes and GD2 (NB-associated marker) were higher on MV from NB patients' BM than in controls. Moreover, CD203a/PC-1 expression on BM-derived MV provide a basis for distinguishing NB patients with high or low BM infiltration. ADO production and consumption of related by-products were significantly higher when assessed on NB patients' MV than those from controls. MV isolated from NB patients' BM significantly downregulated in vitro T cell proliferation. Lastly, NB patients with worse prognosis are identified by a high percentage of CD38 + or CD73 + MV in the BM. In conclusion, ectonucleotidases are present and functional on NB cells, as well as in NB-infiltrated BM and in MV derived from BM. It is reasonable that MV are involved in BM infiltration by NB cells. Therefore, targeting these molecules may widen the therapeutic armamentarium for metastatic NB patients. ARTICLE HISTORY

show abstract

Section: Discussionmentioning

confidence: 78%

Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…ADO effects are associated with immunosuppression either in hematological or solid tumors (and normal immune cells). Indeed, evidence supporting the described mechanisms were confirmed in different normal cells (e.g., T- and B-, NK-, MDSC, among others) as well as in cells hijacked by pathological processes (T-, plasma-, leukemic-, melanoma-, glioblastoma- and non-small lung cancer-cells) [ 49 , 51 , 52 , 53 , 54 ]. In detail, CD56 bright CD16 + NK cells produce ADO through a CD38-mediated pathway.…”

Section: Cd38-controlled Activities and Metabolic Adaptation Durinmentioning

confidence: 85%

The Circular Life of Human CD38: From Basic Science to Clinics and Back

et al. 2020

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

show abstract

“…MM cells home to and expand in the BM, establishing a relationship with BM stromal cells (SCs) (i.e., endothelial cells, fibroblasts, osteoblasts, osteoclasts, and immune cells) [5][6][7][8], thus creating a supportive niche. Inside the niche, the cellular/noncellular components favor MM cell survival through the activation of several biological processes, i.e., angiogenesis, hypoxia, autophagy, metabolism reprogramming, and apoptosis resistance, which gradually modify tumor microenvironment and BMSCs [9][10][11][12][13]. Accordingly, targeting both tumor and nontumor cells is the main goal of the new anti-MM therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

“…CD38 contributes to the catabolism of nicotinamide adenine dinucleotide (NAD + ) involved in several cellular functions, including local immunosuppression [13]. In the BM niche, MM cells reprogram their metabolism that increases NAD + levels yielding lactate and H + [18].…”

Section: Introductionmentioning

confidence: 99%

“…In the BM niche, MM cells reprogram their metabolism that increases NAD + levels yielding lactate and H + [18]. Through its ectoenzymatic activity, CD38 catalyzes the cleavage of NAD + into cyclic adenosine diphosphate (ADP)-ribose, next to ADP-ribose via hydrolase activity [13]. Furthermore, CD38 catalyzes the transglycosilation of nicotinamide adenine dinucleotide phosphate (NADP) and nicotinic acid, to yield nicotinic acid adenine dinucleotide phosphate (NAADP).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma

Saltarella

Desantis

Melaccio

et al. 2020

Cells

View full text Add to dashboard Cite

Daratumumab (Dara) is the first-in-class human-specific anti-CD38 mAb approved for the treatment of multiple myeloma (MM). Although recent data have demonstrated very promising results in clinical practice and trials, some patients do not achieve a partial response, and ultimately all patients undergo progression. Dara exerts anti-MM activity via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and immunomodulatory effects. Deregulation of these pleiotropic mechanisms may cause development of Dara resistance. Knowledge of this resistance may improve the therapeutic management of MM patients.

show abstract

Functional insights into nucleotide-metabolizing ectoenzymes expressed by bone marrow-resident cells in patients with multiple myeloma

Cited by 9 publications

References 145 publications

Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells

Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells

The Circular Life of Human CD38: From Basic Science to Clinics and Back

Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma

Contact Info

Product

Resources

About