Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor-Host Interaction and Therapeutic Perspectives

Abstract

Cancer is still one of the world's most pressing health-care challenges, leading to a high number of deaths worldwide. Immunotherapy is a new developing therapy that boosts patient's immune system to fight cancer by modifying tumor-immune cells interaction in the tumor microenvironment (TME). Extracellular adenosine triphosphate (eATP) and adenosine (Ado) are signaling molecules released in the TME that act as modulators of both immune and tumor cell responses. Extracellular adenosine triphosphate and Ado activate purinergic type 2 (P2) and type 1 (P1) receptors, respectively, triggering the so-called purinergic signaling. The concentration of eATP and Ado within the TME is tightly controlled by several cell-surface ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed in cancer cells, immune cells, stromal cells, and vasculature, being CD73 also expressed on tumor-associated fibroblasts. Once accumulated in the TME, eATP boosts antitumor immune response, while Ado attenuates or suppresses immunity against the tumor. In addition, both molecules can mediate growth stimulation or inhibition of the tumor, depending on the specific receptor activated. Therefore, purinergic signaling is able to modulate both tumor and immune cells behavior and, consequently, the tumor-host interaction and disease progression. In this review, we discuss the role of purinergic signaling in the host-tumor interaction detailing the multifaceted effects of eATP and Ado in the inflammatory TME. Moreover, we present recent findings into the application of purinergic-targeting therapy as a potential novel option to boost antitumor immune responses in cancer.

Keywords: CD39; CD73; P2X7 receptor; immunotherapy; purinergic signaling; tumor microenvironment.

Figure 1

Schematic illustration showing extracellular adenosine triphosphate (eATP) contrasting effects on tumor and host side. eATP can trigger different and opposite effects on both tumor and host cells depending on the cell type and receptor activated. The final result—either stimulating or restraining tumor growth—will depend on the eATP levels, the panel of P2 receptor subtypes and CD39/CD73 expression by tumor and immune cells present in the tumor microenvironment. Overall, eATP is a potent pro-inflammatory mediator, mostly boosting immune cells response.

Figure 2

Schematic illustration exhibiting extracellular adenosine (eAdo) opposing effects on tumor and host side. Likewise extracellular adenosine triphosphate (eATP), eAdo can exert distinct and contrasting effects on both tumor and host cells depending on the cell type and receptor activated. eAdo can also promote tumor cell death via its continuous uptake into the cell. As depicted by eATP, the sum of eAdo levels, the group of P1 receptor subtypes, and CD39/CD73 expression by tumor and immune cells in the tumor microenvironment will dictate the final effect on tumor growth. Overall, eAdo is a potent immunosuppressive nucleoside, mostly inhibiting immune cell responses.

Figure 3

Therapeutic strategies to overcome tumor immune escape and boost cancer immunosurveillance in the tumor microenvironment (TME). In the inflammatory TME, tumor and immune cells interact to produce a favorable immunosuppressive microenvironment. Extracellular adenosine triphosphate (eATP), a pro-inflammatory mediator, accumulates in the TME, but it is rapidly converted to the immunosuppressive factor adenosine (Ado) via the sequential enzymatic activity of CD39 and CD73. Ado acting through A_2A and A_2B receptors inhibits dendritic cells (DCs), NK, and effector T cells activation while it enhances the suppressive function of Tregs, macrophages, and myeloid-derived suppressor cell (MDSC). Strategies by targeting Ado formation, i.e., by blocking CD39/CD73 enzymes and Ado receptors (mainly A_2A) will build up eATP concentration and improve the antitumor immune response. Specifically on DCs, eATP acting through P2X7 receptor will trigger NLRP3 inflammasome activation and IL-1β release with consequent stimulation of CD8⁺ and CD4⁺ lymphocyte-mediated antitumor response, which is a critical step for the efficacy of chemotherapy and radiotherapy. Therefore, combining purinergic-targeting therapies with other anticancer modalities may be a new strategy to overcome immune escape, potentiate antitumor immune response, and consequently restrain tumor growth.