Adenosine Signaling in the Tumor Microenvironment

Antonioli, Luca; Fornai, Matteo; Pellegrini, Carolina; D’Antongiovanni, Vanessa; Turiello, Roberta; Morello, Silvana; Haskó, György; Blandizzi, Corrado

doi:10.1007/978-3-030-47189-7_9

Cited by 21 publications

(19 citation statements)

References 225 publications

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“…The TME is also rich in the ATP hydrolysis derivative extracellular adenosine (eADO) ( Boison and Yegutkin, 2019 ). These two molecules exert opposing actions on the immune system, as, while eATP ( via P2X7R) is pro-inflammatory and promotes anti-tumor immune response ( Kepp et al, 2021 ), adenosine acts as an immunosuppressant, thus facilitating tumor immune escape ( Leone and Emens, 2018 ; Young et al, 2018 ; Allard et al, 2020 ; Antonioli et al, 2021 ). However, the effects of both eATP and eADO are not limited to activity on immune cells as often through the same receptors expressed by either tumor cells or surrounding stroma they also promote cancer growth, vascularization and metastasis ( Di Virgilio et al, 2016 ; Borea et al, 2018 ; Scarpellino et al, 2019 ; Arnaud-Sampaio et al, 2020 ; Sitkovsky, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the context of cancer, the A2AR has been widely studied, emerging as a crucial mediator of eADO effects in the TME ( Ohta et al, 2006 ; Boison and Yegutkin, 2019 ). Its activation potently suppresses both B and T cells’ effector activity while promoting the accumulation of regulatory T cells (Tregs), which are known to be immunosuppressive ( Sorrentino et al, 2013 ; Antonioli et al, 2021 ). Furthermore, stimulation of A2AR, on macrophages populating the tumor lesion, promotes the differentiation of M2-like macrophages, which are the major responsible for the accumulation of vascular endothelial growth factor (VEGF) in the TME and the subsequential angiogenesis ( Sitkovsky et al, 2014 ; Allard et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Marchi

Pegoraro

Turiello

et al. 2022

Front. Cell Dev. Biol.

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ATP and adenosine are key constituents of the tumor niche where they exert opposite and complementary roles. ATP can be released in response to cell damage or actively released by tumor cells and subsequently degraded into adenosine, which accumulates within the tumor microenvironment. Notably, while ATP promotes immune eradicating responses mainly via the P2X7 receptor (P2X7R), extracellular adenosine acts as a potent immune suppressor and facilitates neovascularization thanks to the A2A receptor (A2AR). To date, studies exploring the interplay between P2X7R and A2AR in the tumor microenvironment are as yet missing. Here, we show that, in C57/bl6 P2X7 null mice inoculated with B16-F10 melanoma cells, several pro-inflammatory cytokines, including interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 17 (IL-17), interferon gamma (IFN-γ) were significantly decreased, while the immune suppressant transforming growth factor beta (TGF-β) was almost three-fold increased. Interestingly, tumors growing in P2X7-null mice upregulated tumor-associated and splenic A2AR, suggesting that immunosuppression linked to lack of the P2X7R might depend upon A2AR overexpression. Immunohistochemical analysis showed that tumor cells’ A2AR expression was increased, especially around necrotic areas, and that vascular endothelial growth factor (VEGF) and the endothelial marker CD31 were upregulated. A2AR antagonist SCH58261 treatment reduced tumor growth similarly in the P2X7 wild type or null mice strain. However, SCH58261 reduced VEGF only in the P2X7 knock out mice, thus supporting the hypothesis of an A2AR-mediated increase in vascularization observed in the P2X7-null host. SCH58261 administration also significantly reduced intratumor TGF-β levels, thus supporting a key immune suppressive role of A2AR in our model. Altogether, these results indicate that in the absence of host P2X7R, the A2AR favors tumor growth via immune suppression and neovascularization. This study shows a novel direct correlation between P2X7R and A2AR in oncogenesis and paves the way for new combined therapies promoting anti-cancer immune responses and reducing tumor vascularization.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Marchi

Pegoraro

Turiello

et al. 2022

Front. Cell Dev. Biol.

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“…A growing body of evidence suggests that there is a link between angiogenesis, motility and the adenosinergic pathway [101]. In endothelial progenitor cells (EPC), expression of the C-X-C motif chemokine receptor 4 (CXCR4) is upregulated after ADO treatment, and ADO can subsequently increase EPC migration to the heart after myocardial infarction where it stimulates angiogenesis via A 2B R and CXCR4-dependent mechanisms [102].…”

Section: Migration and Angiogenesismentioning

confidence: 99%

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

Kotulová

Hajdúch

Džubák

2021

IJMS

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A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

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“…The A2AR has been widely studied, emerging as a crucial mediator of eADO effects in the TME (Ohta et al, 2006; Boison and Yegutkin, 2019). Its activation potently suppresses both B and T cells’ effector activity while promoting the accumulation of regulatory T cells (Tregs), which are known to be immunosuppressive (Sorrentino et al, 2013; Antonioli et al, 2021). Furthermore, stimulation of A2AR, on macrophages populating the tumor lesion, promotes the differentiation of M2-like macrophages, which are the major responsibles for the accumulation of vascular endothelial growth factor (VEGF) in the TME and the subsequential angiogenesis (Sitkovsky et al, 2014; Allard et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A2A Receptor contributes to tumor progression in P2X7 null mice

Marchi

Pegoraro

Turiello

et al. 2022

Preprint

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ATP and adenosine are key constituents of the tumor niche where they exert opposite and complementary roles. ATP promotes tumor growth but also immune eradicating responses mainly via the P2X7 receptor (P2X7R), while adenosine acts as a potent immune suppressor and facilitates neovascularization thanks to A2A receptor (A2AR) activity. However, studies exploring the interplay between P2X7R and A2AR in the tumor microenvironment are as yet missing. Here we investigated tumor growth in C57/bl6 P2X7 null mice inoculated with B16-F10 melanoma cells, showing that several pro-inflammatory cytokines (IL1-β, TNF-α, IL-6, IL-12, IL-17, IFN-γ) were significantly decreased while the immune suppressant TGF-β was almost three-fold increased. Interestingly, tumors growing in P2X7-null mice also upregulated tumor-associated and splenic A2AR, suggesting that immunosuppression associated to lack of the P2X7R might depend upon A2AR overexpression. Immunohistochemical analysis showed that tumor cells A2AR expression was increased, especially around necrotic areas, and that VEGF and the endothelial marker CD31 were also upregulated. The A2AR antagonist SCH-58261 reduced tumor growth similarly in the P2X7 WT, or null mice strain. However, SCH-58261only reduced VEGF in the P2X7-KO mice, thus supporting the hypothesis of an A2AR mediated increase in vascularisation in P2X7-null host. SCH-58261 administration also significantly reduced intratumor TGF-β, thus supporting a key immune suppressive role of A2AR in our model. This study shows a novel direct correlation between P2X7R and A2AR in oncogenesis and paves the way for new combined therapies promoting anti-cancer immune responses and reducing tumor vascularization.

show abstract

Adenosine Signaling in the Tumor Microenvironment

Cited by 21 publications

References 225 publications

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

A2A Receptor contributes to tumor progression in P2X7 null mice

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