Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma

Zanoni, Michele; Sarti, Alba Clara; Zamagni, Alice; Cortesi, Michela; Pignatta, Sara; Arienti, Chiara; Tebaldi, Michela; Sarnelli, Anna; Romeo, Antonino; Bartolini, Daniela; Tosatto, Luigino; Adinolfi, Elena; Tesei, Anna; Virgilio, Francesco Di

doi:10.1038/s41419-022-04526-0

Cited by 31 publications

(31 citation statements)

References 62 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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“…Indeed, primary cultures allow for the preservation of the malignant subclones and the genetic and phenotypic cell features [ 104 , 110 , 111 ]. All of these features actively contribute to mimicking the human tumour microenvironment, as well as its contribution to drug response [ 112 ]. Thus, primary cultures represent an important tool for translational research because the preservation of tumour microenvironment makes the data of drug efficacies more realistic than those obtained from in vitro experiments.…”

Section: Precision Medicine In Hnsccsmentioning

confidence: 99%

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

Miserocchi

Spadazzi

Calpona

et al. 2022

JPM

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Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.

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Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma

Cited by 31 publications

References 62 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

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

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