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

Abstract

The regulation of the immune microenvironment within solid tumors has received increasing attention with the development and clinical success of immune checkpoint blockade therapies, such as those that target the PD-1/PD-L1 axis. The metabolic microenvironment within solid tumors has proven to be an important regulator of both the natural suppression of immune cell functionality and the de novo or acquired resistance to immunotherapy. Enzymatic proteins that generate immunosuppressive metabolites like adenosine are thus attractive targets to couple with immunotherapies to improve clinical efficacy. CD38 is one such enzyme. While the role of CD38 in hematological malignancies has been extensively studied, the impact of CD38 expression within solid tumors is largely unknown, though most current data indicate an immunosuppressive role for CD38. However, CD38 is far from a simple enzyme, and there are several remaining questions that require further study. To effectively treat solid tumors, we must learn as much about this multifaceted protein as possible—i.e., which infiltrating immune cell types express CD38 for functional activities, the most effective CD38 inhibitor(s) to employ, and the influence of other similarly functioning enzymes that may also contribute towards an immunosuppressive microenvironment. Gathering knowledge such as this will allow for intelligent targeting of CD38, the reinvigoration of immune functionality and, ultimately, tumor elimination.

High CD38 expression in tumor-infiltrating immune cells is a favorite prognosis factor in esophageal squamous cell carcinoma with perigastric lymph node metastasis

“…Moreover, the anti-CD38 therapy approached its therapeutic goals with acceptable adverse effects in patients with multiple myeloma [34][35][36]. The co-inhibition of CD38 and PD-L1 was supposed to treat solid tumor [6]. Our study found that the expression of CD38 was negatively correlated with PD-L1 expression in tumor cells and positively correlated with the PD-L1 expression in immune cells in patients without perigastric lymph node metastasis.…”

“…Compare to normal cells, though the mRNA and protein expression of CD38 was higher in malignant cells of breast cancer, lung cancer, hepatic cancer and esophageal cancer, and CD38 has been linked to the tumor differentiation, invasion and metastasis, CD38 might exhibit both stimulating and inhibiting effects to tumor development [8,[16][17][18][19]. The function of CD38 was dependent on the cancer type, tumor cell type and interaction with immune cells in the microenvironment [6,8]. CD38 converts NAD + to ADP − ribose (ADPR) and cADPR, which are essential for regulating extracellular metabolites, intracellular Ca2 + level, cell adhesion, and signal transduction pathways [20].…”

“…CD38 is a circumscribed enzyme expressed in tumor cells and active immune cells, such as the T cells, B cells, natural killer (NK) cells and Myeloid-derived suppressor cells (MDSC) [6,7]. CD38 is involved in regulating extracellular metabolism, intracellular Ca 2+ level, cell adhesion, activity of cyclase and hydrolytic enzyme, and signal transduction pathways, participating in the immunity regulation in tumor microenvironment (TME) [6]. CD38 has been reported to play an essential role in the primary and secondary drug resistance of ICI treatment [8].…”

“…However, the function of CD38 is complex [8]. CD38 contributes to tumor growth and immune suppression by regulating tumor immune microenvironment [6].…”

NAD+ Metabolism and Regulation: Lessons From Yeast

“…Supporting this, the combination of PARP inhibitors and Nampt inhibitors was shown to induce synthetic lethality in breast cancer cells [140]. The roles of Nampt and NAD + metabolism in metabolic diseases such as cancers and diabetes have been extensively discussed in several recent reviews [5,6,134,138,[141][142][143]. Here we discuss the roles of NAD + , NAD + biosynthesis enzymes Nmnats and NAD + -dependent sirtuins in select diseases of the nervous system.…”