ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis

Liu, Hong; Kuang, Xinwei; Zhang, Yongchang; Ye, Youqiong; Li, Jialu; Liang, Long; Xie, Zuozhong; Weng, Liang; Guo, Jia; Li, Hui; Ma, Fangyu; Chen, Xiaodan; Zhao, Shuang; Su, Juan; Yang, Nong; Fang, Fang; Xie, Yang; Tao, Juan; Zhang, Jianglin; Chen, Mingliang; Peng, Cong; Sun, Lun‐Quan; Zhang, Xin; Liu, Jing; Han, Leng; Xu, Xiaowei; Hung, Mien‐Chie

doi:10.1016/j.ccell.2020.02.006

Cited by 143 publications

(120 citation statements)

References 41 publications

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“…Unlike adenosine receptor A2AR, A2BR, and A3, one study showed adenosine receptor A1 (ADORA1) signaling axis suppresses tumor PD-L1-mediated immune evasion (94). Downregulation and inhibition of adenosine receptor A1 (ADORA1) significantly induces tumor PD-L1 expression by promoting ATF3 transcriptional activity.…”

Section: Tumor Metabolites Promote Tumor Immune Evasion Adenosinementioning

confidence: 99%

“…Downregulation and inhibition of adenosine receptor A1 (ADORA1) significantly induces tumor PD-L1 expression by promoting ATF3 transcriptional activity. Although the role of adenosine signaling in tumor immunity is different from that in immune cells, the antagonist of the adenosine receptor 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) has demonstrated synergistic effect with PD-1 antibody in melanoma and non-small cell lung cancer (NSCLC) ( 94 ).…”

Section: Tumor Metabolites Promote Tumor Immune Evasionmentioning

confidence: 99%

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Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

Jiang

Hsu

et al. 2020

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.

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Section: Tumor Metabolites Promote Tumor Immune Evasion Adenosinementioning

confidence: 99%

Section: Tumor Metabolites Promote Tumor Immune Evasionmentioning

confidence: 99%

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

Jiang

Hsu

et al. 2020

Front. Oncol.

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“…In addition, altered Ca 2+ influences Ca 2+ /cyclic AMP (cAMP) signaling pathway contributing to the regulation of cytokines [ 35 ]. Both the excretion of cytokines and change in cAMP pathway are associated with tumor progression [ 12 , 36 ]. These findings could be the potential mechanism of DCK regulating the expression of inhibitor receptors and contributing to the progression of a tumor.…”

Section: Discussionmentioning

confidence: 99%

DCK is a promising prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

et al. 2020

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Background: Deoxycytidine kinase (DCK), an enzyme in the nucleoside biosynthetic pathway, can affect the development of immune cells. However, the relationships between the expression of DCK, patient prognosis, and tumor-infiltrating immune cells (TIICs) in hepatocellular carcinoma (HCC) are still unclear. Methods: The expression of DCK in HCC was analyzed through the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The impact of DCK on clinical prognosis was investigated via the Kaplan-Meier plotter and verified in the Gene Expression Profiling Interactive Analysis (GEPIA) databases. The interrelationships between DCK expression and TIICs in HCC were analyzed by the TIMER database. Additionally, the relationship between DCK expression and immune cell gene markers was calculated through TIMER and GEPIA databases. Results: Compared with the adjacent normal tissues, high expression of DCK was observed in HCC tissues. Also, the higher expression of DCK was correlated to poorer prognosis in HCC patients, and it was associated with decreased survival in those with early stage and grade. Moreover, DCK expression was positively correlated with TIICs, including CD4 + and CD8 + T cells, B cells, monocytes, tumor-associated macrophages (TAMs), M1 and M2 macrophages, neutrophils, natural killer cells, and dendritic cells. Specifically, DCK expression levels were significantly associated with diverse immune gene marker sets, including those of Tregs and exhausted T cells.

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“…Recently, it was reported that A1R deletion suppressed melanoma-derived cell growth and induced the inhibition of T cells in co-culture, antagonizing the anti-tumor immune response depending on another A2AR receptor, through a pathway involving overexpression of PD-L1 driven by the transcription factor ATF3 [144]. Taken together, these observations lead us to conclude that actions of ARs are too complex and could be opposite in diverse physiological events.…”

Section: Purines and Evasion Of Immune Attackmentioning

confidence: 91%

Purinergic Signaling in the Hallmarks of Cancer

Campos-Contreras

Dı́az-Muñoz

Vázquez‐Cuevas

2020

Cells

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Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.

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ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis

Abstract: Highlights d ADORA1 inhibition promotes immune escape by regulating tumor PD-L1 via ATF3 d ADORA1 or ATF3 screening may be used to assess PD-1 mAb therapy efficacy d Combination of an ADORA1 antagonist and a PD-1 mAb provides therapeutic benefit

Cited by 143 publications

References 41 publications

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

DCK is a promising prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

Purinergic Signaling in the Hallmarks of Cancer

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