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

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Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor–Host Interaction and Therapeutic Perspectives The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation de Andrade Mello, Paola, Robson Coutinho-Silva, and Luiz Eduardo Baggio Savio. 2017. “Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor–Host Interaction and Therapeutic Perspectives.” Frontiers in Immunology 8 (1): 1526. doi:10.3389/fimmu.2017.01526. http://dx.doi.org/10.3389/ fimmu.2017.01526. Published Version doi:10.3389/fimmu.2017.01526 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493041 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA REVIEW published: 14 November 2017 doi: 10.3389/fimmu.2017.01526 Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor–Host Interaction and Therapeutic Perspectives Paola de Andrade Mello1, Robson Coutinho-Silva 2* and Luiz Eduardo Baggio Savio2* 1 Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, 2Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 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 Edited by: boosts patient’s immune system to fight cancer by modifying tumor–immune cells Salem Chouaib, interaction in the tumor microenvironment (TME). Extracellular adenosine triphosphate Institut Gustave Roussy, France (eATP) and adenosine (Ado) are signaling molecules released in the TME that act Reviewed by: Alessandro Poggi, as modulators of both immune and tumor cell responses. Extracellular adenosine Azienda Ospedaliera Universitaria triphosphate and Ado activate purinergic type 2 (P2) and type 1 (P1) receptors, San Martino (IRCCS), Italy respectively, triggering the so-called purinergic signaling. The concentration of eATP Francois Ghiringhelli, INSERM, France and Ado within the TME is tightly controlled by several cell-surface ectonucleotidases, *Correspondence: such as CD39 and CD73, the major ecto-enzymes expressed in cancer cells, immune Robson Coutinho-Silva cells, stromal cells, and vasculature, being CD73 also expressed on tumor-associated [email protected]; Luiz Eduardo Baggio Savio fibroblasts. Once accumulated in the TME, eATP boosts antitumor immune response, [email protected], while Ado attenuates or suppresses immunity against the tumor. In addition, both [email protected] molecules can mediate growth stimulation or inhibition of the tumor, depending on the specific receptor activated. Therefore, purinergic signaling is able to modulate Specialty section: This article was submitted to both tumor and immune cells behavior and, consequently, the tumor–host interaction Cancer Immunity and and disease progression. In this review, we discuss the role of purinergic signaling Immunotherapy, a section of the journal in the host–tumor interaction detailing the multifaceted effects of eATP and Ado in Frontiers in Immunology the inflammatory TME. Moreover, we present recent findings into the application of Received: 16 September 2017 purinergic-targeting therapy as a potential novel option to boost antitumor immune Accepted: 27 October 2017 responses in cancer. Published: 14 November 2017 Citation: Keywords: purinergic signaling, P2X7 receptor, CD39, CD73, tumor microenvironment, immunotherapy de Andrade Mello P, Coutinho-Silva R and Savio LEB (2017) Multifaceted Effects of Extracellular Adenosine INTRODUCTION Triphosphate and Adenosine in the Tumor–Host Interaction and Cancer is still one of the world’s most pressing health-care challenges, leading to death in an esti- Therapeutic Perspectives. mated number of 600,920 patients per year in the United States (1). However, recent advances in Front. Immunol. 8:1526. cancer immunotherapy have transformed the treatment of several patients, extending and improving doi: 10.3389/fimmu.2017.01526 their lives (2, 3). Immunotherapy is a new developing therapy that boosts patient’s immune system Frontiers in Immunology | www.frontiersin.org 1 November 2017 | Volume 8 | Article 1526 de Andrade Mello et al. Purines Multifaceted Effects in Cancer to fight cancer, by modifying tumor–immune cells interaction in response and Ado attenuates or suppresses immunity on the host the tumor microenvironment (TME) (4). According to the cancer side (38–45), both molecules can mediate growth stimulation or immunoediting concept, the interaction between cancer and inhibition on the tumor cells, depending on the specific receptor immune cells occurs in three essential phases: elimination, equilib- activated (46–52). Regardless, the final effect on tumor growth— rium, and escape—from cancer immune surveillance to immune either beneficial or detrimental—will depend on the eATP/Ado escape (5–7). In the elimination and equilibrium phase innate levels, the panel of P2 and P1 receptors subtypes and CD39/CD73 and adaptive immune system—mainly NK and T cells—mount expression by immune, tumor, and stromal cells in the TME (22). an effective immune response against the highly immunogenic Therefore, despite its complexity and dual behavior, modula- tumors, and allow the less immunogenic ones escape (8–16). This tion of purinergic signaling by targeting eATP/Ado pathways immunologic pressure selects and favors tumor variants resistant appears to be a promising strategy to modify cancer and immune to the immune system to proliferate (immunoevasion) (9, 17). cells cross talk in the TME (24, 36, 53). In this review, we will During this process, both cancer and inflammatory cells release discuss the role of purinergic signaling into the host–tumor several soluble factors such as cytokines, chemokines, growth interaction detailing the multifaceted effects of eATP and Ado factors, matrix-degrading enzymes, and nucleotides that facilitate in the inflammatory TME. Furthermore, we will highlight the tumor immune escape and allow tumor growth, angiogenesis, application of combining purinergic-targeting therapies with invasion, and metastasis (18–22). Therefore, targeting multiple other anticancer treatments as a potential new strategy to over- molecules that avoid immunoevasion and boost antitumor come immune escape, potentiate antitumor immune response, immune responses are the leading paths to successfully treat a and, consequently, restrain tumor growth. whole range of tumor types (3). Among the nucleotides released in the TME, extracellular eATP IN THE TME adenosine triphosphate (eATP) and adenosine (Ado) are potent modulators of both immune and tumor cell response (23, 24). Measurement of eATP levels in different biological context eATP and Ado exert their effects acting through P2 and P1 reveals that healthy tissues present very low levels (10–100 nM) purinergic receptors, respectively, triggering the so-called of this nucleotide in the pericellular space, while in sites of tissue purinergic signaling (25, 26). Purinergic signaling has long damage, inflammation, hypoxia, ischemia, TME or metastases been involved with inflammation and cancer having a pivotal it can reach high levels (hundreds of micromoles per liter) role in modulating cell migration, proliferation, and cell death (24, 54–56). ATP is abundantly released in the extracellular (27, 28). P2 and P1 receptors are expressed by nearly all cell space due to cell death, cell stress, and activation of pannexin/ types (immune and non-immune cells) and differently trigger connexin channels on immune and endothelial cells (54, 57, 58). cell signaling according to their subtypes (29–31). The P2 recep- In these settings, increased levels of eATP are sensed as a “danger tor is subdivided into two separate subfamilies, P2X (P2X1–7) signal” by the innate immune cells resulting in their recruitment ionotropic ion channels receptors and P2Y (P2Y1, P2Y2, to the damaged-tissue site (42, 57, 59–61). Particularly in the P2Y4, P2Y6, and P2Y11–P2Y14) G-protein-coupled receptors TME, eATP acting through P2 receptors boosts the antitumor (25, 26), whereas the P1 receptor family (A1, A2A, A2B, and A3) only immunity at the same time that stimulates endothelial and tumor comprised by G-protein-coupled receptors subtype (32). These cells (27, 36, 42, 48, 60). different purinergic receptors express distinct agonist affinity and specificity, therefore influencing both tumor and immune cells eATP Effect on the Host Side behavior according to the levels of eATP/Ado in TME (33–35). Activation of P2 receptors by eATP shapes various innate and Levels of eATP and Ado are tightly controlled by several adaptive immune responses (30). The P2X and P2Y receptors ectonucleotidases. Among them, CD39 and CD73 are the most expression (either constitutive or upregulated in pathological important ecto-enzymes expressed in cancer cells, regulatory conditions) varies according to the cell type and therefore dictates immune cells and vasculature responsible for modulating puriner- immune cell function, such as metabolism, adhesion, activation, gic signaling within the TME (36, 37). CD39 is a member of the migration, maturation, release of
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