1,721,034 research outputs found
Targeting the adenosine A2b receptor in the tumor microenvironment overcomes local immunosuppression by myeloid-derived suppressor cells
No full textAdenosine A2a receptor agonists as regulators of inflammation: pharmacology and therapeutic opportunities
No full textA2a receptor (A2aR) plays an important role in the regulation of inflammatory and immune responses. The activation of PKA-dependent and/or -independent pathways are responsible for the downmodulation of inflammatory networks and tissue injury. Based on promising recent studies, selective A2aR agonists are under clinical investigations for a wide range of disorders, such as ischemia-reperfusion injury, chronic inflammation, and infectious diseases. Nevertheless, further studies are required to improve our understanding in the ability of A2a receptor agonists to reduce tissue damage during inflammation. Characterization of A2aR-induced signaling pathways will be useful for the development of novel therapeutic strategies in inflammatory/immune diseases
The A2B adenosine receptor: an emerging therapeutic target in cancer
No full textBackground: Adenosine is an ATP metabolite, generated in the extracellular space by the ectonucleotidase CD73. In the tumor microenvironment adenosine impairs anti-tumor immunity, through the Gs-coupled receptors A2A and/or A2B, promoting tumor growth and survival. Blockade of CD73 or A2AR subtype has been shown to improve the anti-tumor immune response. Inhibitors of these targets are currently in Phase I clinical trials in cancer patients. Whilst A2AR is the most thoroughly characterized receptor involved in the immunosuppressive effects of adenosine, A2B is emerging as a potential anti-cancer target.
Materials and methods: To investigate the mechanisms through which the A2BR pharmacological modulators impact the primary tumor growth a syngeneic mouse model of melanoma was used. B16.F10 melanoma-bearing mice were treated with a selective antagonist of A2BR, PSB1115. Myeloid and lymphoid leucocyte populations were analyzed in the tumor tissue, tumor draining lymph node and spleen harvested from control and PSB1115-treated groups. The effects of A2BR modulators were also examined in tumor stroma cells, including endothelial cells and melanoma-associated fibroblasts. The therapeutic potential of the A2BR blocker was tested in combination with some chemotherapeutics, such as dacarbazine.
Results: Our results show that A2BR inhibition with PSB1115 significantly delayed tumor growth in mice. PSB1115 treatment decreased the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment but not in non-tumoral peripheral organs. This effect was associated with an increased numbers of tumor-infiltrating CD8+ T cells and NKT cells, and enhanced levels of IFN-γ and granzyme B. The anti-tumor effects of PSB1115 was indeed lost in melanoma-bearing nude mice lacking of T cells. The effects of A2BR inhibitor was also evaluated on tumor stroma cells. Tumor angiogenesis in PSB1115-treated mice was inhibited and the expression levels of tumor VEGF reduced. Furthermore we found that PSB1115 treatment impacted the function of melanoma-associated fibroblasts in producing FGF2 and CXCL12, which contribute to enhance tumor growth. Treatment of animals with PSB1115 enhanced the anti-tumor activity of dacarbazine and anti-VEGF agents.
Conclusions: Pharmacological blockade of A2BR inhibits the growth of syngeneic melanoma in vivo. PSB1115 treatment decreases the number of tumor MDSCs, increases the number of tumor-infiltrating T lymphocytes, affects tumor angiogenesis and the activation of melanoma-associated fibroblasts. Therefore data from animal studies support the therapeutic potential of A2B blockers in melanoma
Role of plasmacytoid dendritic cells in lung-associated inflammation.
No full textPlasmacytoid Dendritic Cells (pDCs) are important immune orchestrators. One of the most important features of pDCs is the high production of IFN type I that can promote the polarization of T cells towards a Th1 phenotype. Recent evidence has highlighted the relevance of pDCs in therapy for asthma, lung infections and cancer. However, it is to note that pDCs can also participate in suppressive networks via the recruitment of T regulatory cells. Further studies are needed to understand pDCs activity in the lung, not only to elucidate pathological mechanisms, but also to lead towards new therapeutic approaches for lung inflammatory-based diseases. The article also outlines recent patents on plasmacytoid DCs
The adenosinergic system in cancer: Key therapeutic target
No full textHigh amounts of adenosine are released in the tumor mass. Depending on the levels of adenosine, as well as on the receptor subtypes that are expressed by immune cells, adenosine can affect tumor growth in different fashions. Specifically targeting CD73, the rate-limiting enzyme for the extracellular generation of adenosine, or the A3 receptor offers new therapeutic strategies to limit tumor progression
A peptide activating protease activated receptor 2 (PAR2) modulates vascular responses to phenylephrine in vitro and in vivo.
No full textRole of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target
No full textAdenosine receptors are a family of G-coupled receptors which mediate the anti-inflammatory and immune-suppressive effects of adenosine in a damaged tissue. A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression, helping cancer cells to evade immune responses. Tumor cells and/or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A2A receptor, which in turn strongly suppresses an effective T-cell-mediated response, while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells. CD73 inhibitors and A2A antagonists, either as single agents, or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies, are currently in Phase I clinical trial in cancer patients. Recent studies show that A2B receptor plays an important role in mediating the pro-tumor effects of adenosine, since its selective blockade can inhibit tumor growth in some murine tumor models. Targeting A2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment, limiting tumor angiogenesis and metastatic processes. Here, the authors review the current data on involvement of A2B receptor in regulating tumor progression and discuss the development of A2B receptor inhibitors as potential therapeutic agents in cancer treatment
Ecto-5ʹ-nucleotidase (CD73): an emerging role as prognostic factor in allergic sensitization
No full text: Over the years, the importance of the epithelium in the assessment of allergic sensitization and development of allergic diseases has increased. Sensitization to allergens appears to be influenced by genetic and external environmental factors. However, not all subjects exposed to environmental factors that damage epithelial cells suffer from allergic diseases. On this basis, identifying the signaling pathways that characterize the different phenotypes and endotypes of allergy is of high priority for a successful personalized therapy. Ecto-5'-nucleotidase/CD73 is a membrane-bound enzyme responsible for extracellular adenosine accumulation from AMP derived, in turn, from the hydrolysis of extracellular ATP. Current knowledge suggests that CD73 expression and enzymatic activity at epithelial barriers would be of fundamental importance to control the first defense against allergens, by preserving both physical and immunological epithelial barrier functions. Here, we highlight evidence for a crucial role of CD73 in features of allergic sensitization and the potential of this enzyme as prognostic marker and target of therapeutic intervention
The Ecto-5'-Nucleotidase/CD73 Inhibitor, α,β-Methylene Adenosine 5'-Diphosphate, Exacerbates Carrageenan-Induced Pleurisy in Rat
Full text linkThe ecto-5'-nucleotidase (ecto-5'NT/CD73) represents a crucial enzyme for endogenous adenosine generation. Several findings have shown that CD73 plays an important role in regulating vascular permeability and immune cell function. Adenosine 5'-(α,β-methylene)diphosphate (APCP) is a CD73 inhibitor, widely used as pharmacological tool to investigate the role of CD73/adenosine pathway in several in vitro and in vivo models, although it has been also shown to inhibit other ectoenzymes involved in adenosinergic pathway. Here, we evaluated the effect of APCP in the development of inflammation in carrageenan-induced pleurisy model. We found that treatment with APCP (400 μg/rat) significantly increased cell accumulation, exudate formation, and pro-inflammatory cytokine content into the pleural cavity in the acute phase (4 h) of inflammation, with no differences in the sub-acute phase (72 h) except for the regulation of monocyte chemotactic protein-1 levels. In addition, cells collected by pleural lavage fluids of APCP-treated rats, 4 h following carrageenan injection, showed increased ability to migrate in vitro, both in presence and in absence of N-formyl-L-methionyl-L-leucyl-L-phenylalanine as chemotactic stimulus, compared to cells obtained by control rats. Our results demonstrate that APCP exacerbates the early phase of carrageenan-induced pleurisy by controlling pleural effusion and polymorphonuclear migration in vivo and ex vivo. This effect is likely dependent upon CD73 inhibition, although an inhibitory effect of other ectoenzymes cannot be ruled out
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