Anti‐CD73 therapy impairs tumor angiogenesis

Abstract

CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.CD73 is a glycosyl-phosphatidylinositol (GPI)-anchored nucleotidase that catalyzes the hydrolysis of extracellular adenosine monophosphates (AMP) into adenosine. CD73 is found overexpressed in several types of cancer, including bladder cancer, leukemia, glioma, glioblastoma, melanoma, ovarian cancer, colon cancer and breast cancer. 1,2 CD73 overexpression in tumors is at least in part a consequence of the hypoxic nature of the tumor microenvironment. Accordingly, CD73 transcription is induced by hypoxia-inducible factor (HIF)21. 3,4 CD73 expression is also upregulated following loss of estrogen receptor (ER) signaling in breast cancer 5 and epigenetically regulated in melanoma 6 and breast cancer cells. 7 Landmark studies by Sitkovsky et al. demonstrated that extracellular adenosine accumulates in tumors and potently suppresses the function of tumor-infiltrating T cells via A2A adenosine receptors. [8][9][10][11] Inspired by this body of work, studies from our laboratory and others have underscored the therapeutic potential of blocking CD73 for cancer therapy. 12-16 Using CD73-deficient mice and targeted CD73 blockade with a monoclonal antibody (mAb), we demonstrated that anti-CD73 therapy can effectively rescue endogenous and treatment-induced anti-tumor immune responses from the suppressive effects of extracellular adenosine. [12][13][14]

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…A 2A -receptor inhibition has been shown to synergize with the effect of PDL-1 immune checkpoint inhibitors in preclinical tumor models. 41 This treatment combination is currently undergoing clinical trials in numerous …”

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

“…It has been shown that adenosine and other purines promote endothelial proliferation and migration in vitro [24,25], although results in more physiological models of sprouting angiogenesis have been contradictory [7,[26][27][28]. Therefore, we analyzed the role of extracellular purine metabolism on angio-and lymphangiogenesis using a quantitative model of sprouting [29].…”

CD73 Is Associated with Poor Prognosis in High-Grade Serous Ovarian Cancer

“…CD73 is a GPI-anchored nucleotidase that catabolizes the production of extracellular adenosine. Inspired by landmark studies from Sitkovsky and colleagues, we and others have underscored the therapeutic potential of blocking CD73 and adenosine receptors for cancer therapy (12)(13)(14)(15). In the ID8 mouse model of ovarian cancer, Zhang and colleagues reported that CD73 gene silencing, or targeted blockade of CD73 with a monoclonal antibody (mAb) or a small molecule inhibitor, enhances antitumor T-cell responses and improves animal survival (11).…”