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

Abstract

The tumor microenvironment (TME) consists of extracellular matrix proteins, immune cells, vascular cells, lymphatics and fibroblasts. Under normal physiological conditions, tissue homeostasis protects against tumor development. However, under pathological conditions, interplay between the tumor and its microenvironment can promote tumor initiation, growth and metastasis. Immune cells within the TME have an important role in the formation, growth and metastasis of tumors, and in the responsiveness of these tumors to immunotherapy. Recent breakthroughs in the field of cancer immunotherapy have further highlighted the potential of targeting TME elements, including these immune cells, to improve the efficacy of cancer prognostics and immunotherapy. CD38 and CD157 are glycoproteins that contribute to the tumorigenic properties of the TME. For example, in the hypoxic TME, the enzymatic functions of CD38 result in an immunosuppressive environment. This leads to increased immune resistance in tumor cells and allows faster growth and proliferation rates. CD157 may also aid the production of an immunosuppressive TME, and confers increased malignancy to tumor cells through the promotion of tumor invasion and metastasis. An improved understanding of CD38 and CD157 in the TME, and how these glycoproteins affect cancer progression, will be useful to develop both cancer prognosis and treatment methods. This review aims to discuss the roles of CD38 and CD157 in the TME and cancer immunotherapy of a range of solid tumor types.Cells 2020, 9, 26 2 of 18 inhibit tumor growth and development [5,9]. Surface glycoproteins expressed by immune infiltrates can be used as biomarkers for classification of the immune cells. These glycoproteins also influence the pro-or anti-tumor activity of immune cells. Thus, the presence and functions of glycoproteins on the surface of tumor immune infiltrates are currently subjected to intense study.CD38 and CD157 are two such glycoproteins of particular interest in the field of immunotherapy. They are coded by contiguous gene sequences found on human chromosome 4, and are thought to originate from gene duplication. These gene sequences share similarities in terms of length and the organization of introns and exons, and the resultant proteins share similar functions [10]. CD38 and CD157 function as both receptors and ectoenzymes, and belong to the same family of nicotinamide adenine dinucleotide (NAD+) converting enzymes.CD38 is involved in lymphocyte activation, proliferation and adhesion. Initially thought to be expressed only by thymic lymphocytes, it has since been found to be ubiquitously expressed by immune cells, including B lymphocytes, natural killer cells and monocytes; and its expression varies across both lymphoid and non-lymphoid tissues [10,11]. In contrast, CD157 is mainly expressed by cells derived from the myeloid lineage, and in particular by neutrophils and monocytes. CD157 is also expressed by a wide range of non-lymphoid tissues, including vascular endothelium, kidney collecting tubu...

Targeting Immunometabolism Mediated by CD73 Pathway in EGFR-Mutated Non-small Cell Lung Cancer: A New Hope for Overcoming Immune Resistance

“…In addition to traditional pathways mediated by CD39/CD73, an alternative enzymatic cascade has been recently reported and includes ectoenzymes such as CD38 (NAD + nucleosidase), CD203α (ecto-nucleotide pyro-phosphatase phosphodiesterase 1) and CD73 (70,71), thus participating to the composition of the so-called "purinergic milieu" (72). Indeed, in the search of a better understanding of the mechanisms involved in the acquired immunotherapy resistance, it has been reported that the unresponsiveness to PD-1/PD-L1 inhibition in lung murine models is probably mediated by the tumor up-regulation of CD38 enzyme, which is induced by all-trans retinoic acid and IFN-β in the TME.…”

High CD38 expression in tumor-infiltrating immune cells is a favorite prognosis factor in esophageal squamous cell carcinoma with 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 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 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].…”

Host CD39 Deficiency Affects Radiation-Induced Tumor Growth Delay and Aggravates Radiation-Induced Normal Tissue Toxicity

“…ATP was already shown being able to activate the VEGF receptor in the absence of VEGF, and the P2YR-VEGFR2 interaction and the resulting signal transduction are critical determinants of vascular homoeostasis and tumor-mediated angiogenesis (107). Moreover, CD38dependent signaling can impact on (tumor) angiogenesis (55,108). Herein, CD38 turned out to be an important regulator for the intrinsic expression of key angiogenic factors (100,109,110).…”