Role of adenosine A2b receptor overexpression in tumor progression

Sepúlveda, César; Palomo, Iván; Fuentes, Eduardo

doi:10.1016/j.lfs.2016.10.008

Cited by 48 publications

(40 citation statements)

References 143 publications

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“…CD38 activation of adenosine receptors by alltrans-retinoic acid (ATRA) inhibits T cell function via adenosine expression [103]. Because adenosine is a strong immunosuppressive substance, it inhibits effector T cell immune function by cytokine secretion and inhibits T cell proliferation [104]. CD73 binding to adenosine receptor 2A on T cells produces adenosine, inhibiting the immune response to PD-1/PD-L1 blockade [105].…”

Section: T Cell Activation Disordersmentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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Section: T Cell Activation Disordersmentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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“…A2BR is the predominant receptor expressed in multiple tumor types with several fold higher expression over normal tissue (reviewed in [105]). A number of studies have shown that A2BR activation can enhance tumor growth [84,85,[106][107][108] and that targeting A2BR at the genetic level can reverse this effect [84,106,108].…”

Section: Expression Of Adenosine Receptors and Signaling Pathways In mentioning

confidence: 99%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

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The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

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“…The A 2B AR subtype has been recently linked to cancer aggressiveness ( Mittal et al, 2016 ; Sepúlveda et al, 2016 ) and fibrotic processes of the heart ( Ryzhov et al, 2014 ; Phosri et al, 2017 ), kidney ( Roberts et al, 2014 ; Wilkinson et al, 2016 ) and lung ( Zhou et al, 2011 ; Karmouty-Quintana et al, 2012 ; Karmouty-Quintana et al, 2013 ). A 2B AR couples to G αs proteins, resulting in the activation of adenylyl cyclase (AC) and an increase in intracellular cyclic AMP (cAMP) levels that subsequently activate protein kinase A (PKA) ( Schulte and Fredholm, 2003 ; Sun and Huang, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The A2B Adenosine Receptor Modulates the Epithelial– Mesenchymal Transition through the Balance of cAMP/PKA and MAPK/ERK Pathway Activation in Human Epithelial Lung Cells

et al. 2018

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The epithelial-mesenchymal transition (EMT) is a complex process in which cell phenotype switches from the epithelial to mesenchymal one. The deregulations of this process have been related with the occurrence of different diseases such as lung cancer and fibrosis. In the last decade, several efforts have been devoted in understanding the mechanisms that trigger and sustain this transition process. Adenosine is a purinergic signaling molecule that has been involved in the onset and progression of chronic lung diseases and cancer through the A2B adenosine receptor subtype activation, too. However, the relationship between A2BAR and EMT has not been investigated, yet. Herein, the A2BAR characterization was carried out in human epithelial lung cells. Moreover, the effects of receptor activation on EMT were investigated in the absence and presence of transforming growth factor-beta (TGF-β1), which has been known to promote the transition. The A2BAR activation alone decreased and increased the expression of epithelial markers (E-cadherin) and the mesenchymal one (Vimentin, N-cadherin), respectively, nevertheless a complete EMT was not observed. Surprisingly, the receptor activation counteracted the EMT induced by TGF-β1. Several intracellular pathways regulate the EMT: high levels of cAMP and ERK1/2 phosphorylation has been demonstrated to counteract and promote the transition, respectively. The A2BAR stimulation was able to modulated these two pathways, cAMP/PKA and MAPK/ERK, shifting the fine balance toward activation or inhibition of EMT. In fact, using a selective PKA inhibitor, which blocks the cAMP pathway, the A2BAR-mediated EMT promotion were exacerbated, and conversely the selective inhibition of MAPK/ERK counteracted the receptor-induced transition. These results highlighted the A2BAR as one of the receptors involved in the modulation of EMT process. Nevertheless, its activation is not enough to trigger a complete transition, its ability to affect different intracellular pathways could represent a mechanism at the basis of EMT maintenance/inhibition based on the extracellular microenvironment. Despite further investigations are needed, herein for the first time the A2BAR has been related to the EMT process, and therefore to the different EMT-related pathologies.

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Role of adenosine A2b receptor overexpression in tumor progression

Cited by 48 publications

References 143 publications

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

The A2B Adenosine Receptor Modulates the Epithelial– Mesenchymal Transition through the Balance of cAMP/PKA and MAPK/ERK Pathway Activation in Human Epithelial Lung Cells

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