CD38 as an immunomodulator in cancer
Yanli Li1, Rui Yang1, Limo Chen**,2 & Sufang Wu*,1
1 Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, PR China
2 Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
*Author for correspondence: wsf [email protected]
**Author for correspondence: [email protected]

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

First draft submitted: 24 April 2020; Accepted for publication: 24 July 2020; Published online: 28 August 2020
• • • • •
Keywords: biomarker cancer immunotherapy CD38 immune checkpoint therapy immunomodulation tumor microenvironment

Human CD38 was originally defined in the late 1970s while investigators conducted a project aimed at probing the cell surface of human leukocytes using murine monoclonal antibodies (mAbs). It was described as T10 at that moment because of its reactivity with the OKT10 antibody [1,2]. T10 was subsequently vested with CD38 in the 1980s at the Second International Workshop of White Cell Differentiation Antigens [3]. Then, a cDNA clone for human CD38 was isolated from a mixture of four different lymphocyte cDNA libraries expressed transiently in COS cells and screened by panning with mAb [4]. The CD38 gene encodes a Type 1I transmembrane glycoproteia with a short N-terminal cytoplasmic tail and monomorphic features among different lineages [5].
CD38 protein was often referred to as a cell activation marker. However, accumulating evidence suggests that CD38 is a multifunctional molecule. Importantly, CD38 was shown to have several immunologically relevant functions in vitro and in vivo. It has been extensively investigated in hematologic malignancies. An mAb targeting CD38 has been developed and achieved great success in the immunotherapy of multiple myeloma, and today more and more research focuses on its role in cancer, especially in cancer immunotherapy.

Biology of CD38
CD38 is a 45 kDa Type II transmembrane glycoprotein (mCD38), which contains a cytoplasmic (∼21 aa), transmembrane (∼22 aa) and extracellular (∼257 aa) domain. In addition to the existence of mCD38, human CD38 is also found in a 39-kDa soluble form (sCD38), which has been detected both in vitro and in vivo. It
shares immunological and catalytic features with mCD38 [6]. As an ectoenzyme, CD38 catalytic activity depends on the disulfide bonds that stabilize the structure of the enzyme [7]. CD38 displays ADP-ribosyl cyclase 1 and
cyclic ADP-ribose hydrolase activities [8,9]. ADP-ribosyl cyclase catalyzes production of cADPR, a Ca2+ mobilizing metabolite, from NAD+ [10]. cADPR is known to increase intracellular Ca2+concentration ([Ca2+]i) by releasing Ca2+ from the intracellular stores or by Ca2+ influx through plasma membrane Ca2+ channels [10]. CD38 also
binds hyaluronic acid, a component of the extracellular matrix [11,12], and serves as a cell surface receptor for CD31, a member of the immunoglobulin (Ig) superfamily, which regulates leukocyte adhesion and transmigration [13]. The CD38 gene has 5694 bases and maps to chromosome 4p15 [4,14]. The CD38 protein has 300 amino acid residues and consists of a short intracellular N-terminal domain, a transmembrane helix and a long C-terminal

extracellular catalytic domain [15]. Signal cascades triggered by CD38 lean upon its localization to lipid rafts and relationship with signaling complexes in immune cells [16]. For example, CD38 is functionally dependent on the TCR/CD3 complex in human T cells [17].

Expression of CD38
CD38 is widely expressed by many cell types [9], including most thymocytes, activated T cells [1,18] and B cells, plasma cells [19], NK cells [20] and dendritic cells (DCs) [21]. In contrast, most mature resting lymphocytes show a low expression level of surface CD38 [22]. CD38 is highly expressed in most cases of myeloma [23] and many cases of AIDS-associated lymphoma. CD38 expression is also present in acute lymphoblastic leukemia (ALL), acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma [24]. In nonhematopoietic tissues, such as kidney, cardiac, pancreatic, spleen, lung and liver cells [5,16], CD38 is also expressed and associated with a number of diseases, such as heart disease [25,26], respiratory syncytial virus infection [27], HIV infection [28,29], allergic airway disease [30], systemic lupus erythematosus [31], diabetes mellitus [32,33], fetomaternal tolerance [34], autism spectrum disorders [35], glomerular sclerosis [36], inflammatory bowel disease [37], rheumatoid arthritis [38] and cancers.

CD38 & cancers
Apart from the important bifunctional ectoenzymatic activities that contribute to intracellular calcium mobiliza- tion, CD38 has multiple functions, including ectoenzymatic activity and receptor-mediated regulation of cell adhesion and signal transduction [5,9,39]. CD38 at present is also a multifunctional protein contributing to can- cer progression [40]. It is identified as a prognostic factor of acute myeloid leukemia [41], chronic lymphocytic leukemia [42,43], prostate cancer [44,45], pancreatic cancer [46], acute B lymphoblastic leukemia [47], lung cancer [48], hepatocellular cancer [49] and triple-negative breast cancer [50]. CD38 is also expressed heterogeneously in colorectal cancer (CRC) [51] but does not depend on tumor localization, tumor grade and presence of metastases. CD38 is also a putative functional marker for side population cells in human nasopharyngeal carcinoma cell lines [52] and may serve a carcinogenic role in nasopharyngeal carcinoma cells by affecting energy metabolism [53]. CD38 inhibitor inhibits glioma progression [54]. In prostate cancer, CD38 inhibits tumor metabolism and proliferation
by reducing cellular NAD+ pools [55]. CD38 is highly expressed [56] and enhances the proliferation and inhibits
the apoptosis of cervical cancer cells by affecting mitochondrial functions [57]. High expression of CD38 predicted
favorable prognosis in esophageal squamous cell carcinoma patients [58]. CD38 expression or absence showed prognostic value for lung cancer [59]. CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells [60]. Thus, it was concluded that anti-CD38 treatment may have therapeutic potential in lung cancer [60]. In addition, based on the finding, a polyethylene terephthalate (PET) tracer based upon CD38 expression tracking was developed and its utility was verified in murine models [61].

CD38 & immune cells
T cells
Ample evidence indicates that CD38 expression on normal T cells changes according to the activation status of the cells. CD38 has been documented as an ‘intermediate’ T-cell activation marker [62]. Using mAbs to cell surface antigens and fluorescent cell sorter analysis, Fox et al. [63] studied peripheral blood lymphocyte subsets after bone marrow transplantation and demonstrated that transplant patients showed an increased number of T cells with
cell surface phenotype CD38. CD38+CD4+ T cells are associated with a ‘naive-like’ effector phenotype, higher cytolytic potential, and a strongly impaired ability to produce IFN-γ and other cytokines and CD38-CD4+ T cells can differentiate into CD38+ CD4+ T cells upon stimulation [64]. T cells with reduced surface expression of the CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis and
altered mitochondrial dynamics that vastly improved tumor control. Interfering expression of CD38 improved tumor control, and thus strategies targeting the CD38-NAD+ axis could increase the efficacy of antitumor adoptive T-cell therapy [65].

Treg cells
CD4+CD25+ regulatory T cells (Treg cells) play a ciritical role in immunological self-tolerance. They represent a small subpopulation of T cells originating in the thymus, which is dependent on the expression of the forkhead family
transcription factor Foxp3. Treg cells have immunosuppressive function. They generally suppress or downregulate

induction and proliferation of effector T cells [66]. CD38 is expressed on Treg cells, and its expression level is related to the suppressive function of Tregs. CD38 knockout mice present with a loss of Foxp3+ Tregs [67,68], and CD38 antibodies, such as isatuximab, modulate the frequency and function of Tregs dependent on CD38 [69]. On
the contrary, Tregs with CD38 high expression showed superior suppressive activity compared with CD38 low Tregs [70–72]. Hence, CD38 may be used to define Tregs with high suppressive activity, and targeting Tregs by CD38 mAb to restore effective antitumor response represents a promising treatment strategy [73].

B cells
CD38 is expressed from the earliest stages of B-cell development. In humans, immature B cells, germinal center (GC) B cells and plasma cells express abundant CD38 [5]. The levels of CD38 on the surface of GC B cells suggested that it could be involved in the process of selection of GC B cells. In addition, CD38 expression increases with B-cell maturation [74]. Mature virgin and memory B cells express low levels of the molecule. It was reported that
CD38 ligation inhibits the growth of immature B lymphoid cells in the bone marrow microenvironment [75]. Cord blood and adult bone marrow hematopoietic stem cells with a Lin-CD34+CD38low phenotype but not Lin-CD34+CD38high cells have the ability to generate both B-1 and B-2 cells [76]. Therefore, CD38 plays a novel
role during the regulation process of B differentiation and maturation. Moreover, soluble CD38 significantly prolongs the lifespan of memory B-cell responses [77]. Infiltration of CD38 B cells is also suggested as a predictor for poor clinical outcomes of acute cellular rejection in renal allograft [78].

Dendritic cells
CD38 was reported to represent a novel human DC marker. It is downmodulated during the differentiation of monocytes into immature DCs and expressed again upon maturation. Moreover, CD38 maintains its function as a receptor in mature myeloid dendritic cells (MDCC) and mediates signaling. It participates in regulation of the immune response through the induction of IL-12 and regulation of CD83 expression in mature MDCC (mMDCC). When CD38 signaling was suppressed, monocyte-derived DCs exhibited a more immature phenotype and reduced ability to present antigens and produce IL-12 [79]. Subsequently, it was further suggested that the localization of CD38 in lipid rafts and its multiple interactions with signaling receptors (CD83, CD11b and CCR7) rule innate and adaptive immune responses by tuning DC migration, survival and Th1-polarization ability [80]. Similarly, it was found that the splenocytes from CD38-knockout mice secreted reduced IFN-γ and increased IL-4 in wild-type mice, indicating that CD38 has a role in the development of protective immune responses in Th1 polarization and participates in cell-mediated immunity [81]. It was also suggested that CD38 may be involved in the DC function of alleviating asthma via restoration of the Th1/Th2 balance, thus providing a novel strategy for asthma therapy. CD38 also influences both innate and adaptive immune responses by regulating the trafficking of DCs to the sites of inflammation [82].

Macrophages
CD38 mediates LPS-induced macrophage activation. The CD38 expression level could be upregulated by LPS in a time- and dose-dependent manner. Knocking down or blockade of CD38 in macrophages could suppress LPS-induced macrophage M1 polarization through inhibiting NF-κB signaling activation [83]. CD38 is involved in Fcγ receptor activation-mediated phagocytosis through its recruitment to the phagosome and mobilization of
cADPR-induced intracellular Ca2+and store-operated extracellular Ca2+ influx [84]. In hepatocellular carcinoma,
CD38 was frequently co-expressed with the macrophage-specific marker CD68 in tumor-associated macrophages. In addition, CD38+CD68+ macrophage density was associated with improved prognosis after surgery. It may serve as a supplement for routine diagnostic work [49]. CD38 upregulation on bone marrow macrophages in response to
inflammatory stimuli negatively impacts their differentiation toward the osteoclast lineage. It is possible that CD38 may serve as a regulator of cell fate; that is, it may impede osteoclast formation but augment the immune response.

Other immune cells
NK cells are a type of cytotoxic lymphocyte that mediates natural cytotoxicity and antibody-dependent cellular cytotoxicity. CD38 is highly expressed on NK cells [71]. It has been reported that CD38 engagement promotes activation and cytotoxic responses by human NK cells [85,86]. Accordingly, NK cells are reduced by CD38 mAb treatment in a rapid, reversible, dose- and concentration-dependent manner [87]. However, CD38 cannot signal by itself; its receptor function is rescued by functional and physical associations with CD16 in NK cells [85,88].

Myeloid-derived suppressor cells (MDSCs), a population of immature immune cells with several protumorigenic functions, are known to support the progression of multiple types of cancer through immunosuppression, angio-
genesis, tumor cell survival and metastasis [89]. The expression of CD38 on MDSCs has been reported in multiple myeloma [90] and in a murine model of esophageal cancer [91]. In CRC, the CD38+ monocytic MDSCs from CRC patients were found to be immunosuppressive. CRC patients who previously received treatment had significantly higher CD38+ monocytic and polymorphonuclear MDSC levels. This may provides a rationale for an attempt to target monocytic MDSCs with an anti-CD38 mAb in metastatic CRC patients [91].

Immunotherapy targeting CD38
Therapeutic antibodies have been applied to directly target tumor cells for killing for more than three decades. A notable common characteristic of therapeutic antibodies is the importance of the IgG Fc domain, which functions as a bridge between specific antibody and immune cells to trigger effector functions through their engagement of Fc receptor (FcR) family members. All of the effector cells express a significant amount of different FcRs, and the mAbs can bind to FcRs to induce cytotoxicity. Fc domains and FcRs play an important role in therapeutic antibodies in malignancy because they determine whether they directly target tumor cells or alternatively target the immune system, modulating either positive or negative regulatory pathways [92]. CD38 has been considered as a potential target for immunotherapy in multiple myeloma since the early 1990s, although efforts ultimately failed despite promising preclinical results [93]. Daratumumab, a human CD38 IgG1 mAb, was approved by the US FDA in 2015 for treatment of patients with multiple myeloma. Isatuximab is another humanized IgG1 mAb targeting CD38 that similarly shows promising single-agent activity in multiple myeloma [94]. Daratumumab binds to an unique epitope presenting on CD38 molecular with high affinity and specificity. It was first described in 2011 by de Weers et al. [95], they developed the CD38 Abs by immunization of HuMAb mice with purified HA-CD38 recombinant protein alone or alternating with CD38-transfected NIH-3T3 cells [95]. Daratumumab binds CD38 on myeloma cells and results in rapid cell death through multiple immune-mediated mechanisms, including complement- dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis, and the induction of apoptosis through Fc-mediated crosslinking between the Fc region of the antibody and Fcγ
receptors expressed on immune effector cells, as well as modulation of CD38 enzyme activity [96]. In addition, daratumumab has also immunomodulatory effects through the eradication of CD38+ immunosuppressive cells, an elevation of helper and cytotoxic T cells, antiviral and alloreactive functional T-cell responses and increased T-cell
clonality [71].
CD38 not only represents a promising target for mAb-based immunotherapy of multiple myeloma [24,97–100] but also is considered an attractive and nearly universal target in the treatment of hematologic malignancies today. Bride et al. [101] recently carried out a preclinical study by testing daratumumab in a large panel of T-cell ALL patient-derived xenografts and found striking efficacy in 14 of 15 different patient-derived xenografts, suggesting that daratumumab is a promising novel therapy for pediatric T-cell ALL patients [101].
Accumulating large-scale studies of human cancerous samples found CD38 expression in a subpopulation of tumors exhibiting a high cytolytic T-cell score, and immunotherapies should be more powerful in these tumors. These findings provide an opportunity to expand and improve the efficacy of immune checkpoint blockading
in cancer treatment. Verma et al. [102] found that PD-1 blockade before antigen priming abolished therapeutic outcomes. Nonresponding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces therapeutic resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Our group revealed that upregulation of CD38 on tumor
cells is a major mechanism of resistance to anti-PD-1 or PD-L1 therapy. Our data showed that tumor-bearing mice taking PD-1 or PD-L1 blocking treatment develop resistance by means of CD38 upregulation. In addition, upregulation of CD38 expression is mediated by all-trans retinoic acid and IFN-β in the tumor microenvironment.
We also observed that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling in vitro and in
vivo. CD38 blockading serves as an effective strategy to overcome the anti-PD-1 or PD-L1 treatment resistance.
Combined therapy of daratumumab and anti-PD-1 or anti-PD-L1 in lung cancer animal models dramatically suppressed primary tumor growth and metastasis. Therefore, we concluded that dual blockading of CD38 and anti-PD-(L)1 is a rational combination to prevent immune resistance to PD-1/PD-L1 checkpoint therapy and improve the response rate and treatment efficacy for lung cancer patients [103]. Further, we also found that the resistance to combination therapy of anti-PD-1 and anti-CTLA-4 occurs over time, which is associated with CD38

upregulation on tumor cells. Combined PD-1 and CTLA-4 blockade eradicates CD38-deficient tumors in immune competent mice. Combined anti-PD-1/CTLA-4 with sequential CD38 blockade results in a favorable antitumor immune microenvironment, exhibiting an enrichment of CD103+ DCs in tumors (unpublished data).
Discussion & future perspective
The current review highlights investigations into the function of CD38, which is a novel receptor and ectoenzyme that plays a critical role of immunomodulation in a cancer microenvironment. Therapeutic results in multiple myeloma indicate that the anti-CD38 antibodies may have relevant immunotherapeutic properties. Along with the anti-CD38 mAb daratumumab and isatuximab, there are many anti-CD38 compounds in development for treatment of multiple myeloma and other malignancies. However, it remains difficult to reconcile the use of CD38 as a tumor target because of its almost ubiquitous presence on the surface of normal cells. Thus, a concept was proposed by some experts several years ago that an antibody may exert different effects on the tumor target and simultaneously with effector cells with multiple functions. Differences in the surface levels of CD38 (very high on multiple myeloma and low on effectors) may account for its distinct functional effects [104]. However, considering that the certainty of this is unclear, more research is necessary. Apart from the preceding, CD38 mAbs represent powerful tools that will, no doubt, enable investigators to explore more deeply and widely into the application of mAb therapy.

Author contributions
The concept and design was conducted by Y Li. Y Li and R Yang drafted the manuscript. Critical revision of the manuscript for important intellectual content was conducted by L Chen and S Wu. S Wu provided the funding support. All authors read and approved the final manuscript.
Financial & competing interests disclosure
This work was supported by the Shanghai Municipal Natural Science Foundation (no. 18ZR1430500). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

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•• We concluded in this article that dual blockading of CD38 and anti-PD-1(anti-PD-L1) is a rational combination to prevent immune resistance to PD-1/PD-L1 checkpoint therapy and improve the response rate and treatment efficacy for lung cancer
patients.
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•• This review discussed the different effects exerted by the same antibody on the tumor target and simultaneously with effector cells with multiple functions.CD38 inhibitor 1