Anti-CD73 in cancer immunotherapy: awakening new opportunities

Abstract

In recent years, cancer immunotherapy made significant advances due to a better understanding of the principles underlying tumor biology and immunology. In this context, CD73 is a key molecule, since via degradation of adenosine monophosphate into adenosine, endorses the generation of an immunosuppressed and pro-angiogenic niche within the tumor microenvironment that promotes the onset and progression of cancer. Targeting CD73 results in favorable antitumor effects in pre-clinical models and combined treatments of CD73 blockade with other immune-modulating agents (i.e. anti-CTLA-4 mAb or anti-PD1 mAb) is particularly attractive. Although there is still a long way to go, anti-CD73 therapy, through the development of CD73 monoclonal antibodies, can potentially constitute a new biologic therapy for cancer patients. In this review, we discuss the link between CD73 and the onset, development and spread of tumors, highlighting the potential value of this molecule as a target and as a novel biomarker in the context of personalized cancer therapy.

Keywords: CD73; adenosine; cancer; immunotherapy; tumor microenvironment.

Figure 1

Structure and role of CD73 in the extracellular metabolic pathways. CD73 is characterized by an N-terminal domain containing binding sites for zinc and cobalt ions and a C-terminal domain containing the AMP binding site. The C-terminal domain is linked to the plasma membrane through a GPI anchor. These two domains are connected by a short α helix. Once released in the extracellular milieu, ATP and ADP are converted into AMP via ecto enzyme CD39 and further into adenosine through CD73. Extracellular NAD⁺ is converted into ADPribose and nicotinamide (Nam) by NAD⁺-glycohydrolases and ADP ribosyl-transferases (ARTs). ADP ribose can be further split to form AMP by ADP-ribose pyrophosphatase, subsequently converted to adenosine by CD73. In addition, NAD⁺ can also be degradated by NAD⁺ diphosphatase to produce nicotinamide mononucleotide (NMN) and AMP.