A<sub>2A</sub>R Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

Huang, Jiaqi; Zhang, Di; Bai, Yu; Peng, Yang; Xing, Ligang; Yu, Jinming

doi:10.7150/jca.43966

Cited by 12 publications

(9 citation statements)

References 46 publications

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“…Therefore, targeting both receptors has the potential to prove more efficacious than a stand-alone therapeutic strategy. Finally, based on previous studies, a combination of P2X7R and A2AR directed drugs could also prove beneficial in association with traditional chemotherapy ( Pegoraro et al, 2020 ; Sitkovsky, 2020 ) or irradiation ( Huang et al, 2020 ; Zanoni et al, 2022 ).…”

Section: Discussionmentioning

confidence: 94%

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: Discussionmentioning

confidence: 94%

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Marchi

Pegoraro

Turiello

et al. 2022

Front. Cell Dev. Biol.

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“…Moreover, one should consider that when targeting P2X7R within cancer, it might also influence A2AR activity and vice-versa and, thus, that an anti-tumoral therapeutic strategy targeting both receptors has the potential to prove more efficacious than a stand-alone one. Finally, based on previous studies, a combination of P2X7R and A2AR directed drugs could also prove beneficial in association with traditional chemotherapy (Pegoraro et al, 2020;Sitkovsky, 2020) or irradiation (Huang et al, 2020;Zanoni et al, 2022).…”

Section: Discussionmentioning

confidence: 94%

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.

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“…Their development closely correlates with adenosine levels and corresponds with poor prognosis by facilitating tumor‐mediated immune escape. [ 32 ] After different treatments, tumors in each group were harvested and analyzed ( Figure A). Representative MDSC dot plots (CD11b + Gr‐1 + ) showed changes in the proportion of MDSC infiltration after various treatments (Figure 7B).…”

Section: Resultsmentioning

confidence: 99%

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

Liu

et al. 2022

Advanced Science

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The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine‐A2AR negative feedback pathway is highlighted during photothermal‐induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal‐induced ICD process. It is possible to achieve a robust ICD‐based immunotherapy via targeting the adenosine‐A2AR metabolic pathway. In this regard, an A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to enable tumor‐specific delivery and photothermal‐induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8+ T lymphocyte infiltration, and reducing the myeloid‐derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials.

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A_2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

Cited by 12 publications

References 46 publications

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

A2A Receptor contributes to tumor progression in P2X7 null mice

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

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A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

Cited by 12 publications

References 46 publications

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

A2A Receptor contributes to tumor progression in P2X7 null mice

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

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A_2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model