The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets

Abstract

Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection-type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized "immune checkpoint mediator" that interferes with anti-tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic-targeting therapies and forecast how these might develop in combination with other anti-cancer modalities.

Keywords: T cells; cancer inflammation; immunity; immunotherapies monocytes/macrophages; tumor.

Figure 1. Effect of ATP on immune cells and vascular endothelium within tumors

ATP impacts a variety of cells upon engagement of P2 receptors and results in the initiation of those pathways predominantly resulting in heightened inflammation and regulatory cell inhibition. Further, ATP effects result in T cell activation and promote Th17 cell differentiation upon induction of IL-23 and IL-1b from myeloid cells and monocyte-macrophages. ATP inhibits Tregs, Tr1 and B cells, whilst favoring chemotaxis of NK cells and neutrophils, M1-type macrophage deviation and DC maturation. ATP also modulates a variety of processes linked to the activation of endothelial cells, inflammation and platelet-mediated thrombosis. In the tumor microenvironment, boluses of high extracellular concentrations of ATP as with tumor necrosis act as “danger signals”, resulting in the recruitment of innate immune cells and boosting anti-tumor cell immunity. In contrast, for unclear reasons, low concentrations and repeated exposure to ATP may be paradoxically associated with immunosuppressive manifestations, trophic effects and enhanced tumor growth (339).

Figure 2. Effect of CD39/CD73 expression and adenosine generation within tumors

In response to hypoxia and other factors (see Table 1), cells in the tumor microenvironment acquire or increase adenosine-generating capabilities, largely through the expression of CD39 and CD73 ectonucleotidases and scavenging of extracellular ATP. Cells expressing CD39 and/or CD73 include tumor cells, cancer-associated fibroblasts (CAF), endothelial cells, Foxp3+ Tregs, Tr1 cells, Th17 cells, γδ T cells, NK cells, invariant (i)NKT cells, effector and memory T cells, B regulatory cells (Breg), myeloid-derived suppressor cells (MDSC), macrophages and neutrophils, inter alia. CD39 and CD73 expression results in the accumulation of micromolar concentrations of adenosine capable of activating both high-affinity A2a and low-affinity A2b receptors. This molecular mechanism in turn increases tumor cell survival and metastasis, promotes angiogenesis, prevents thrombosis, increases fibrosis, enhances the suppressive function of Tregs, Tr1, macrophages and MDSC. This effect also promotes antigen tolerance, inhibits lymphocyte effector function and prevents memory T cells from differentiation into effector cells and all of these factors facilitate tumor growth.