A2AR limits IL-15-induced generation of CD39+ NK cells with high cytotoxicity

Kang, Guijie; Zhao, Xin; Sun, Jian; Cheng, Chen; Wang, Cen; Liu, Tao; Zong, Lu; Yin, Wenwei; Cong, Jingjing; Li, Jing; Wang, Xuefu

doi:10.1016/j.intimp.2022.109567

Cited by 5 publications

(2 citation statements)

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“…Targeting this ADO-receptor results in reduced metastasis, improved tumor control and delayed tumor initiation in experimental models, by enhancing NK-mediated cytotoxic activity in a PRF1 and GZMB-dependent manner ( 42 , 110 ). Furthermore, during infection and cancer, A2AR engagement seems to inhibit via IL-15 signaling blockade, the generation of human CD39+NK cells endowed with a potent degranulation capacity and overexpression of IFNγ and TNFα ( 111 ).…”

Section: Discussionmentioning

confidence: 99%

The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer

Zohair,

Chraa,

Rezouki

et al. 2023

Front. Immunol.

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BackgroundThe crosstalk between the immune system and cancer cells has aroused considerable interest over the past decades. To escape immune surveillance cancer cells evolve various strategies orchestrating tumor microenvironment. The discovery of the inhibitory immune checkpoints was a major breakthrough due to their crucial contribution to immune evasion. The A2AR receptor represents one of the most essential pathways within the TME. It is involved in several processes such as hypoxia, tumor progression, and chemoresistance. However, its clinical and immunological significance in human breast cancer remains elusive.MethodsThe mRNA expression and protein analysis were performed by RT-qPCR and immunohistochemistry. The log-rank (Mantel-Cox) test was used to estimate Kaplan-Meier analysis for overall survival. Using large-scale microarray data (METABRIC), digital cytometry was conducted to estimate cell abundance. Analysis was performed using RStudio software (7.8 + 2023.03.0) with EPIC, CIBERSORT, and ImmuneCellAI algorithms. Tumor purity, stromal and immune scores were calculated using the ESTIMATE computational method. Finally, analysis of gene set enrichment (GSEA) and the TISCH2 scRNA-seq database were carried out.ResultsGene and protein analysis showed that A2AR was overexpressed in breast tumors and was significantly associated with high grade, elevated Ki-67, aggressive molecular and histological subtypes, as well as poor survival. On tumor infiltrating immune cells, A2AR was found to correlate positively with PD-1 and negatively with CTLA-4. On the other hand, our findings disclosed more profuse infiltration of protumoral cells such as M0 and M2 macrophages, Tregs, endothelial and exhausted CD8+ T cells within A2ARhigh tumors. According to the Single-Cell database, A2AR is expressed in malignant, stromal and immune cells. Moreover, it is related to tumor purity, stromal and immune scores. Our results also revealed that CD8+T cells from A2ARhigh patients exhibited an exhausted functional profile. Finally, GSEA analysis highlighted the association of A2AR with biological mechanisms involved in tumor escape and progression.ConclusionThe present study is the first to elucidate the clinical and immunological relevance of A2AR in breast cancer patients. In light of these findings, A2AR could be deemed a promising therapeutic target to overcome immune evasion prevailing within the TME of breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer

Zohair,

Chraa,

Rezouki

et al. 2023

Front. Immunol.

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“…Early studies suggested that NK cell-dependent cytotoxicity was inhibited by CD73 + tumors leading to enhanced tumor metastasis ( 37 , 38 ). Subsequent research revealed that CD73-A 2A R activity suppressed NK cell maturation ( 39 ) and inhibited IL-15-induced NK cytotoxicity ( 40 ). Moreover, CD73 + NK cells within large tumors possessed immune-regulatory function via STAT3-induced IL-10, which suppressed CD4 T cell proliferation and IFN-γ production ( 41 ).…”

Section: Cd73-adenosinergic Pathway As a Critical Icmentioning

confidence: 99%

Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy

et al. 2023

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The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.

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IL-15 as a key regulator in NK cell-mediated immunotherapy for cancer: From bench to bedside

Vahidi,

Zabeti Touchaei,

Samadani

2024

International Immunopharmacology

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A2AR limits IL-15-induced generation of CD39+ NK cells with high cytotoxicity

Cited by 5 publications

References 45 publications

The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer

The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer

Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy

IL-15 as a key regulator in NK cell-mediated immunotherapy for cancer: From bench to bedside

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