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.

Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

“…4a). The concentration range reached in vitro was similar to ADO amounts in tumors in vivo (50-500 ng/ml) (de Andrade Mello et al, 2017). Inhibition of connexin channelfunction by CBX and Cx43 knockdown both reduced the extracellular levels of ADO (by 26-42%), AMP (by 40-41%), ADP (by 60-64%) and ATP (by 28-52%) ( Fig.…”

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

“…Since striking evidence indicates that (MSC‐derived) IDO contributes to tumor immune escape,15, 16, 17 our study focussed on ATP‐enhanced IDO expression in MSCs and its impact on lymphocyte proliferation which was assessed by culturing PBL in conditioned media derived from MSCs stimulated with predominant factors within inflammatory necrotic tissue of tumor, that is, IFNγ as a prototype of inflammation‐associated cytokines plus ATP36, 37 as a crucial DAMPs family member which is found at thousand times higher concentrations in tumor tissue 31, 32, 33…”

“…Since striking evidence indicates that (MSC-derived) IDO contributes to tumor immune escape, [15][16][17] our study focussed on ATP-enhanced IDO expression in MSCs and its impact on lymphocyte proliferation which was assessed by culturing PBL in conditioned media derived from MSCs stimulated with predominant factors within inflammatory necrotic tissue of tumor, that is, IFNγ as a prototype of inflammationassociated cytokines plus ATP 36,37 as a crucial DAMPs family member which is found at thousand times higher concentrations in tumor tissue. [31][32][33] We applied ATP concentrations which are found within (necrotic) tumor tissue, in order to mimic the in vivo situation. As demonstrated here, ATP-stimulated MSCs were capable of reducing PBL proliferation by more than 60% (from 41% to 16%) compared to the condition without ATP (Figure 3), this effect was closely related to IDO expression and subsequent kynurenine production ( Figure 2).…”

“…The sudden decrease in oxygen tension in the vicinity of the developing tumor along with the severe impairment of perfusion pressure in the tumor are expected to serve as a stimulus for the increases in release of erythrocyte ATP pools into the blood plasma in a stimulus‐secretion manner. Thus, about thousand times higher ATP concentrations (e.g., 100 μM) are found within tumor microenvironment when compared to normal tissue (10–100 nM) 31, 32, 33…”

“…Thus, about thousand times higher ATP concentrations (e.g., 100 μM) are found within tumor microenvironment when compared to normal tissue (10-100 nM). [31][32][33] Based on the described observations, we aimed to study the influenced of ATP on immunoregulatory capacities of MSCs, in order to better characterize the immunosuppressive milieu of tumor to pave the way for a possible treatment strategy targeting tumor's microenvironment.…”