CD38 and Regulation of the Immune Response Cells in Cancer

Abstract

Cancer is a leading cause of death worldwide. Understanding the functional mechanisms associated with metabolic reprogramming, which is a typical feature of cancer cells, is key to effective therapy. CD38, primarily a NAD + glycohydrolase and ADPR cyclase, is a multifunctional transmembrane protein whose abnormal overexpression in a variety of tumor types is associated with cancer progression. It is linked to VEGFR2 mediated angiogenesis and immune suppression as it favors the recruitment of suppressive immune cells like Tregs and myeloid-derived suppressor cells, thus helping immune escape. CD38 is expressed in M1 macrophages and in neutrophil and T cell-mediated immune response and is associated with IFNγ-mediated suppressor activity of immune responses. Targeting CD38 with anti-CD38 monoclonal antibodies in hematological malignancies has shown excellent results. Bearing that in mind, targeting CD38 in other nonhematological cancer types, especially carcinomas, which are of epithelial origin with specific anti-CD38 antibodies alone or in combination with immunomodulatory drugs, is an interesting option that deserves profound consideration.

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1. Introduction

Cancer immunotherapy has progressed enormously since the identification of immune checkpoints. The list of putative stimulatory and inhibitory checkpoints so far clearly established is extensive: ICOS/ICOS-L, GTR/GTR-L, CD27/CD70, CD40/CD40-L, DNAM-1/CD155, MHC-II/LAG-3, PD1-L1/2, Galectin-9/TIM-3, and many more [1]. The search for new immune checkpoint targets is now centered towards the adenosinergic pathway and its metabolite adenosine (ADO), that support immune suppression within the tumor microenvironment (TME) [2, 3] as it limits the functionality of T, Dendritic, and NK cells, as well as macrophages and neutrophils [4].

The accumulation of adenosine in the TME is partly dependent on two ectoenzymes entangled in canonical and noncanonical pathways [5]. One is the ectonucleoside triphosphate diphosphohydrolase (NTPDase, CD39) that converts ATP released by cell lysis or by exocytosis of ATP-containing vesicles via transport vesicles or via lysosomes into AMP, and the other is ecto-5-nucleotidase (Ecto5¨NTase, CD73) that dephosphorylates AMP into adenosine [6]. The generation of adenosine by a noncanonical pathway begins with NAD in a reaction run by the multifunctional transmembrane protein CD38 [7].

CD38 has come into consideration as its involvement in adenosine-mediated immunosuppression within the tumor microenvironment has been established [8]. CD38 is a multifunctional ectoenzyme that functions as a nicotinamide adenine dinucleotide (NAD+) glycohydrolase and catalyzes the synthesis and degradation of cADPR affecting calcium signaling and release, thus decreasing extracellular NAD+, altering calcium cascade and deeply contributing to adenosine-mediated immune suppression (Figure 1), which alters the activity of T, NK, and dendritic cells and attracts migration of suppressor cells like MDSCs, Tregs, and Bregs [9–11]. The effect upon immune cells is mainly via modulation of FasL expression [12–14]. Alterations in CD38/FasL regulated apoptosis have been reported in myeloma [15, 16] and in NK cells of gastric cancer patients [17, 18]. We have recently gathered evidence that suggests that the overexpression of some tight junction proteins in gastric cancer cells affects CD38-related FasL expression and activity on NK cells. Our aim was to emphasize the role of CD38 on the immune suppression of some malignant neoplasms and to emphasize its role as an interesting target for cancer immunotherapy [19].

[figures omitted; refer to PDF]

1.1. CD38 Structure

CD38 is a 45 kDa type II transmembrane glycoprotein with a single transmembrane segment near its N-terminus. It shares a 20–30% sequence identity with Aplysia ADP-ribosyl cyclase, BST-1, also termed CD157, and a GPI-anchored protein found in Schistosoma mansoni. It is formed by two identical monomers that favor a physiologically stable structure with a pocket at the middle of the cleft, that is, the enzyme active site. The crystal structure of the extramembrane domain, which is fully active enzymatically and is crystallized as head-to-tail dimers, has been well determined [20, 21]. It is expressed in high densities on plasma cells, plasmablasts, natural killer cells, plasmacytoid dendritic cells, and activated B and T lymphocytes in healthy subjects and in hematological tumors including multiple myeloma [22].

1.2. CD 38 Function

CD38 functions as a lymphocyte receptor and transducer of signals and an ectoenzyme that generates cyclic adenosine diphosphate-ribose involved in intracellular calcium mobilization (Figure 1). First thought to be expressed only on thymocytes and activated T cells, CD38 was later found to be widely expressed on B cells, circulating monocytes, dendritic cells, granulocytes, plasma cells, both resting and circulating NK cells, neutrophils, and granulocytes. CD38 is also found on the surface of erythrocytes and platelets, where it plays an essential role, together with platelet/endothelial cell adhesion molecule 1 (CD31), in the microenvironment retention of cancer cells [22]. CD38 is also expressed in the cytoplasm and nucleus of nonlymphoid cells such as normal prostatic epithelial cells, pancreatic islet cells, smooth and striated muscle cells, renal tubules, retinal gangliar cells, and cornea.

As a surface receptor, CD38 is necessary for the activation and proliferation of immune cells. Its IFNγ and TNFα induce its expression in macrophages and dendritic cells [23]. It establishes a weak and dynamic interaction with the nonsubstrate ligand CD31, in an interaction necessary for leukocyte adhesion and migration. CD38 has a very small cytoplasmic tail suggesting it is unable to initiate a signaling cascade and so it associates with other signaling receptors such as TCR/CD3 in T cells, BCR (CD19/CD21) in B cells, and CD16/CD61 in NK cells. In addition, CD38 ligation with a counter ligand induces the expression and secretion of IL-1β, IL-6, IL-10, and IFNγ from monocytes and T cells. NAADP, produced through the enzymatic activity of CD38 [24], regulates T cell activation, proliferation, and chemotaxis.

CD38 is found in recycling endosomes that contain perforin and granzymes in the immunological synapse when the TCR of cytotoxic T cells is engaged. CD38 is expressed on membrane rafts where it promotes cell signaling via AKT and ERK activation and it is exported out of the cells through the exocytic pathway. CD38 association with the signaling complex CD16/CD61 in the NK cell membrane has a critical role in transducing activating signals. CD38^highCD8⁺ T cells suppress the proliferation of CD38⁻CD4⁺ T cells [25], thus indicating its capacity to modulate T cell subsets with regulatory properties. CD38 signaling upon ligation induces IL-1β, IL-6, and IL-10 secretion and enhanced IL-12 production in synergy with IFNγ in dendritic cells [26, 27].

High CD38 expression in immune cells such as T regs, B regs, MDSCs, and CD16-CD56 + NK cells contribute to a change in their immune function [28–30]. A typical example of the latter is represented by the CD4+CD25^highFOX3+ Treg cells with high CD38 expression that define a suppressive subset of Tregs in multiple myeloma and non-Hodgkin lymphoma via cytokine dependent mechanisms. However, CD31- Tregs depicted reduced immune suppressive activity that indicates the importance of CD38/CD31 interaction in Treg mediated immunosuppression [31]. CD38^high B reg cells produce IL-10, which inhibits T naïve cell differentiation to Th1 and Th17 cells while supporting the proliferation of T regs [32, 33]. The immunosuppressive role of myeloid-derived suppressor cells (MDSCs) is strongly expanded in the cancer microenvironment [29], which is well documented. CD38 expression is considered as a marker of MDSCs activity and CD38^highMDSCs have more prominent immune suppressive effects. At the same time, MDSCs promote neovascularization and tumor invasion (Figure 2).

[figure omitted; refer to PDF]

Daratumumab reduces suppressive cell types in the multiple myeloma tumor microenvironment [52] as it reduces CD38 expression, but as treatment progresses, it also increases the resistance to treatment. Though this reduction is transient, it is regained in 3 to 6 months after the drug infusion. Another important concern is the reduction of CD38+ NK cells even after the first infusion. Though CD38 expression is low, NK cells retain their activity and proliferate normally [88, 89]. In such a case, reinfusion of ex vivo expanded autologous NK cells can be used.

To overcome Daratumumab mediated resistance, the use of new drugs such as a synthetic derivative of all-trans retinoic acid, Tamibarotene (a.k.a Am80), that upregulates CD38 or anti-CD38 antibodies with different mechanisms of action such as Isatuximab, Felzartamab, or Mezagitamab is recommended [90].

Isatuximab is an IgG1 monoclonal antibody that induces apoptosis of tumor cells and ADCC; it binds to a specific discontinuous epitope containing amino acids located opposite to the catalytic site of CD38, thus almost completely inhibiting cyclase activity in a dose-dependent manner [91]. Continuous Isatuximab treatment did not cause a reduction in CD38 receptor expression in H929, MM1S, OPM2, and RPMI-8226 multiple myeloma cell lines. Furthermore, Isatuximab treated cells did not show the clustering of CD38 in polar aggregates that lead to the release of CD38 in microvesicles, an effect that conduces to Daratumumab resistance [92]. Isatuximab substantiated great antitumor activity alone or in combination with dexamethasone and immunomodulatory imide drugs that include lenalidomide, pomalidomide, and iberdomide [93].

Mezagitamab (TAK-079) is a cytolytic IgG1 anti-CD38 monoclonal antibody, which effectively removes CD38+ B cell lines by antibody-dependent or complement-dependent cytotoxicity [94].

Felzartamab (MOR202) is a Human Combinatorial Antibody Library derived human IgG1 anti-CD38 monoclonal antibody that, once attached, attracts natural killer cells, triggers ADCC and ADCP but not CDC, and shows synergistically enhanced cytotoxicity with Bortezomib and Lenalidomide.

Other anti-CD38 agents are currently being evaluated. CAR-T/TCR-T, Multi-CAR-T, TAK-573, TAK-169, T-007, AMG 424, and GBR 1342 are in phase 1/2 clinical development, while others like HexaBody-CD38, CD38-ARM (KP1196, KP1237), TSK011010/CID103, STI-5171, Anti-CD38/IGF-1 R bsAb scFV, Anti-CD38 SIFbod, CAR38-MILs, CD38 DART, and Actinium-225 are in preclinical developmental stages. The significant number of potential candidates under development points to the importance of CD38 in the control of several malignancies.

Because of what has been mentioned, the efficacy of anti-CD38 antibodies in many other cancers is being evaluated in preclinical and initial stages of clinical trials (Table 1).

2. Conclusion

CD38 has dual functions as an ectoenzyme and as a surface receptor that promotes migratory phenotypes and signaling cascades responsible for the activation and proliferation of various immune cells.

Both canonical and noncanonical pathways contribute to adenosine synthesis. However, is targeting CD38 alone sufficient to resolve ADO induced immunosuppression? CD38 expresses ubiquitously in immune populations like T cells, NK cells, and dendritic cells; therefore, targeting CD38 would reduce anti-inflammatory response and rejuvenate antitumor activity of immune cells. But the interconnecting links between CD38, CD39, and CD73 or with downstream adenosine receptors and the persistence of any compensatory mechanism available against CD38 depletion has to be further investigated. It is clear that the enzymatic and the surface receptor functions of CD38 are distinct from each other, and there is insufficient data available to justify which function of CD38 should be targeted for effective immune function restoration and hence, tumor elimination. Nevertheless, the development of anti-CD38 monoclonal antibodies has redefined the treatment landscape due to their ability to normalize immune cells function, thus triggering antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity, antibody-dependent cellular phagocytosis of opsonized CD38+ cells, and direct apoptosis via FCγ receptor-mediated crosslinking. As it has been clearly stated by Morandi et al.[93]: CD38 is a receptor with modulatory functions on immune regulatory cell subsets that warrants deeper analysis.

Acknowledgments

Special thanks are due to Dr. Leopoldo Santos Argumedo, Department of Molecular Biomedicine, Cinvestav, IPN, Mexico for his guidance. Sanyog Dwivedi is a PhD student from the Department of Molecular Biomedicine, Cinvestav-IPN, and receives a CONACYT CVU grant 871712. This work was supported by PAPIIT-UNAM grants IN221519 and IN218019.

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