CD73, Tumor Plasticity and Immune Evasion in Solid Cancers

Abstract

Regulatory networks controlling cellular plasticity, important during early development, can re-emerge after tissue injury and premalignant transformation. One such regulatory molecule is the cell surface ectoenzyme ecto-5′-nucleotidase that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine (eADO). Ecto-5′-nucleotidase (NT5E) or cluster of differentiation 73 (CD73), is an enzyme that is encoded by NT5E in humans. In normal tissue, CD73-mediated generation of eADO has important pleiotropic functions ranging from the promotion of cell growth and survival, to potent immunosuppression mediated through purinergic G protein-coupled adenosine receptors. Importantly, tumors also utilize several mechanisms mediated by CD73 to resist therapeutics and in particular, evade the host immune system, leading to undesired resistance to targeted therapy and immunotherapy. Tumor cell CD73 upregulation is associated with worse clinical outcomes in a variety of cancers. Emerging evidence indicates a link between tumor cell stemness with a limited host anti-tumor immune response. In this review, we provide an overview of a growing body of evidence supporting the pro-tumorigenic role of CD73 and adenosine signaling. We also discuss data that support a link between CD73 expression and tumor plasticity, contributing to dissemination as well as treatment resistance. Collectively, targeting CD73 may represent a novel treatment approach for solid cancers.

A three‐dimensional microenvironment alters CD73 expression in cervical cancer

“…Unlike the majority of solid cancer types, the expression of CD73 in cervical tumours is decreased in comparison to normal tissue. 34,35 Interestingly, the same is observed in other tumours of the genitourinary system, for example, ovarian serous cystadenocarcinoma, testicular germ cell tumours, endometrial carcinoma, uterine carcinosarcoma, bladder carcinoma, kidney chromophobe and prostate adenocarcinoma. 35 Therefore, the similarity of our results analysing cervical tumour spheres in vitro with data from these two recent studies of bioinformatics shows that the CSC model is capable to represent some characteristics of the in vivo tumours.…”

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

“…For example, the extracellular metabolism of ATP into adenosine through the CD38-NPP1-CD73 axis, the CD39-CD73 axis, and the NDPK/NME/NM23 axis is well-documented target system for tumor treatment [32]. CD73 could be a critical regulator that promotes tumor progression in an immune-independent manner, such as tumor stemness, epithelial-tomesenchymal transition (EMT), and therapy resistance [32,33]. Our data supported the concept that CD73-induced generation of adenosine promotes the Warburg effect and tumor growth in gastric cancer.…”

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…AP deregulation in cancer has been principally linked to ADO accumulation in the TME that promotes regulatory T-cells (Tregs) activity and polarization of myeloid cells to immunosuppressive and pro-angiogenic phenotypes and affects NKs and effector T cells (CD8+), thus enhancing tumor growth. Many studies have reported that increased expression of CD73 in cancer relates to different outcomes, such as progression, poor prognosis, metastasis, and weak response to chemotherapy agents [ 116 ]. Although ADO signaling has been poorly investigated in MPM, available data support a role for AP in MPM immune-suppression.…”