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

  • ️Tue Jan 01 2019

Review

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

Jessica M Konen et al. Cells. 2019.

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.

Keywords: cancer therapy; ectoenzymes for NAD and ATP metabolisms; immune suppression.

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Conflict of interest statement

J.M.K. and J.J.F. declare no conflicts of interest. D.L.G. serves on scientific advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi and Janssen and has received research support from Janssen R&D, Takeda, Ribon Therapeutics and AstraZeneca.

Figures

Figure 1
Figure 1

CD38 catalyzes the first step towards adenosine formation from nicotinamide adenine dinucleotide (NAD+). NAD+ present within the tumor microenvironment is catalyzed into adenosine diphosphate ribose (ADPR)—or cyclic ADPR (cADPR), not shown—by CD38. This is the first step in an alternative adenosine generating pathway, with the canonical pathway involving CD39 catalyzing adenosine triphosphate (ATP) to adenosine monophosphate (AMP). AMP is then generated from ADPR by CD203. Both pathways rely on CD73 to convert AMP into the final product adenosine, which can then promote immunosuppression in T cells via adenosine receptor 2A or 2B signaling cascades.

Figure 2
Figure 2

The expression of CD38 within a complex solid tumor microenvironment. The schematic highlights the diversity of CD38 expression within solid tumors, including on the tumor cells as well as resident and infiltrating immune cell populations. As it stands, there are several areas of research necessitating further studies for better understanding of the impact of CD38 targeting in these tumors. Because CD38 functions on T cells, natural killer (NK) cells, and dendritic cells, anti-CD38 treatment may actually prevent the activity of these anti-tumor immune cells and thus decrease efficacy of this treatment strategy (yellow). Additionally, there are a multitude of ways to effectively target CD38, either through blocking antibodies with or without enzymatic inhibition or via small molecule inhibitors which inhibit NADase activity of CD38 (red). Which treatment strategy would be the most efficacious in solid tumors remains a major unknown. Another complicating factor is the potential for compensatory mechanisms which could overcome CD38 inhibition, such as the canonical adenosine generating pathway utilizing CD39 and CD73 (green). Lastly, CD38 likely requires a combinatory treatment strategy in solid tumors to prevent resistance and improve efficacy; thus, what agents to combine with CD38-targeting agents and the timing of these combinations requires future work to best utilize these agents in the treatment of solid tumors (blue).

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