CD38 in Adenosinergic Pathways and Metabolic Re-programming in Human Multiple Myeloma Cells: In-tandem Insights From Basic Science to Therapy

Abstract

Tumor microenvironments are rich in extracellular nucleotides that can be metabolized by ectoenzymes to produce adenosine, a nucleoside involved in controlling immune responses. Multiple myeloma, a plasma cell malignancy developed within a bone marrow niche, exploits adenosinergic pathways to customize the immune homeostasis of the tumor. CD38, a multifunctional protein that acts as both receptor and ectoenzyme, is overexpressed at all stages of myeloma. At neutral and acidic pH, CD38 catalyzes the extracellular conversion of NAD + to regulators of calcium signaling. The initial disassembly of NAD + is also followed by adenosinergic activity, if CD38 is operating in the presence of CD203a and CD73 nucleotidases. cAMP extruded from tumor cells provides another substrate for metabolizing nucleotidases to signaling adenosine. These pathways flank or bypass the canonical adenosinergic pathway subjected to the conversion of ATP by CD39. All of the adenosinergic networks can be hijacked by the tumor, thus controlling the homeostatic reprogramming of the myeloma in the bone marrow. In this context, adenosine assumes the role of a local hormone: cell metabolism is adjusted via low- or high-affinity purinergic receptors expressed by immune and bone cells as well as by tumor cells. The result is immunosuppression, which contributes to the failure of immune surveillance in cancer. A similar metabolic strategy silences immune effectors during the progression of indolent gammopathies to symptomatic overt multiple myeloma disease. Plasma from myeloma aspirates contains elevated levels of adenosine resulting from interactions between myeloma and other cells lining the niche and adenosine concentrations are known to increase as the disease progresses. This is statistically reflected in the International Staging System for multiple myeloma. Along with the ability to deplete CD38 + malignant plasma cell populations which has led to their widespread therapeutic use, anti-CD38 antibodies are involved in the polarization and release of microvesicles characterized by the expression of multiple adenosine-producing molecules. These adenosinergic pathways provide new immune checkpoints for improving immunotherapy protocols by helping to restore the depressed immune response.

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

“…CD38 affects cell metabolism (Cantó et al, 2015), and thus increased CD38 expression can affect T cell function in multiple diseases including leukemias (D'Arena et al, 2001), cancers (Chatterjee et al, 2018), and viral infections (Hua et al, 2014). In multiple myeloma, in which CD38 expression predicts a poor prognosis, CD38 degrades NAD to produce adenosine and leads to effector T cells exhaustion through the adenosine receptor (Horenstein et al, 2019). A recent study demonstrated that increased NAD in the presence of low levels of CD38 switches the intratumoral CD4 T cells into effector Th1/17 cells by enhancing glutaminolysis (Chatterjee et al, 2018).…”

The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors

“…It is almost ubiquitously expressed on multiple immune populations, including T cells, NK cells, and dendritic cells, and a whole body CD38 knockout (KO) mouse demonstrates defects in dendritic cell and neutrophil migration, insufficient T cell priming and diminished humoral immunity [14,15]. CD38 has been extensively studied for its role in hematological malignancies, including chronic lymphocytic leukemia [16,17] and multiple myeloma [17][18][19]. Research on CD38 and its involvement in chronic inflammatory diseases, such as rheumatoid arthritis [20,21] and asthma [22,23], indicates that the aberrant expression and hyperactivity of CD38 can tip immune responses towards disease pathology.…”

The Roles of CD38 and CD157 in the Solid Tumor Microenvironment and Cancer Immunotherapy

“…CD203a can also use NAD+ directly as a substrate to form AMP. AMP is then phosphorylated to adenosine by CD37 [6,21,22]. Extracellular adenosine then binds to adenosine receptors on immune cells, including T cells, natural killer cells, neutrophils, macrophages and dendritic cells, preventing their activation [6,18].…”