Release of adenosine-induced immunosuppression: Comprehensive characterization of dual A2A/A2B receptor antagonist

•Adenosine is an immunosuppressive metabolite engaging A2 receptors on immune cells.•Dual A2A/A2B antagonist liberates lymphoid and myeloid cells from immunosuppression.•SEL330-639 is potent at high adenosine concentration due to slow dissociation rate.•Reversal of immunosuppression is a key factor...

Full description

Saved in:
Bibliographic Details
Published in:International immunopharmacology 2021-07, Vol.96, p.107645-107645, Article 107645
Main Authors: Dziedzic, Katarzyna, Węgrzyn, Paulina, Gałęzowski, Michał, Bońkowska, Magdalena, Grycuk, Karolina, Satała, Grzegorz, Wiatrowska, Karolina, Wiklik, Katarzyna, Brzózka, Krzysztof, Nowak, Mateusz
Format: Article
Language:English
Subjects:
Adenosine
Antagonist
Antigen presentation
Antigens
Binding
CD4 antigen
CD8 antigen
Cyclic AMP response element-binding protein
Cytokines
Cytotoxicity
Drug discovery
Gene expression
GPCR
Immune checkpoint inhibitors
Immune response
Immune system
Immunopharmacology
Immunosuppression
Inflammation
Interleukin 12
Interleukin 2
Metabolites
Mimicry
Natural killer cells
Phosphorylation
Receptors
Toxicity
Tumor microenvironment
Tumor necrosis factor-α
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:•Adenosine is an immunosuppressive metabolite engaging A2 receptors on immune cells.•Dual A2A/A2B antagonist liberates lymphoid and myeloid cells from immunosuppression.•SEL330-639 is potent at high adenosine concentration due to slow dissociation rate.•Reversal of immunosuppression is a key factor in enhancing immunotherapy.•SEL330-639 should be effective as anti-adenosine cancer immunotherapy drug. Immunosuppression is one of the main mechanisms facilitating tumor expansion. It may be driven by immune checkpoint protein expression, anti-inflammatory cytokine secretion or enhanced metabolic enzyme production, leading to the subsequent build-up of metabolites such as adenosine. Under physiological conditions, adenosine prevents the development of tissue damage resulting from a prolonged immune response; the same mechanism might be employed by tumor tissue to promote immunosuppression. Immune cells expressing A2A and A2B adenosine receptors present in an adenosine-rich environment have suppressed effector functions, such as cytotoxicity, proinflammatory cytokine release, antigen presentation and others, making them inert to cancer cells. This study was designed to investigate the dual antagonist potential of SEL330-639 to abolish adenosine-driven immunosuppression. SEL330-639 has slow dissociation kinetics. It inhibits cAMP production in human CD4+ cells, CD8+ cells and moDCs, which leads to diminished CREB phosphorylation and restoration of antitumor cytokine production (IL-2, TNFα, IL-12) in multiple primary human immune cells. The aforementioned results were additionally validated by gene expression analysis and functional assays in which NK cell line cytotoxicity was recovered by SEL330-639. Adenosine-driven immunosuppression is believed to preclude the effectiveness of immune checkpoint inhibitor therapies. Hence, there is an urgent need to develop new immuno-oncological strategies. Here, we comprehensively characterize SEL330-639, a novel dual A2A/A2B receptor antagonist effective in both lymphoid and myeloid cell populations with nanomolar potency. Due to its tight binding to the A2A and A2B receptors, this binding is sustained even at high adenosine concentrations mimicking the upper limit of the range of adenosine levels observed in the tumor microenvironment.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2021.107645