Dataset Information

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.

ABSTRACT: Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection-type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized "immune checkpoint mediator" that interferes with anti-tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic-targeting therapies and forecast how these might develop in combination with other anti-cancer modalities.

SUBMITTER: Allard B

PROVIDER: S-EPMC5338647 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.

Allard Bertrand B Longhi Maria Serena MS Robson Simon C SC Stagg John J

Immunological reviews 20170301 1

Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection-type processes or blocking suppressive pathways. Extrac ...[more]

PMID: 28258700

Similar Datasets

Project description:Synapsed cells can communicate using exocytosed nucleotides like adenosine triphosphate (ATP). Ectonucleotidases localized to synaptic junctions degrade nucleotides into metabolites like adenosine monophosphate (AMP) or adenosine. Oftentimes nucleotide degradation occurs in a sequential manner, of which ATP degradation by CD39 and CD73 is a representative example. Here, CD39 first converts ATP and adenosine diphosphate (ADP) into AMP, after which AMP is dephosphorylated into adenosine by CD73. Hence, the concerted activity of CD39 and CD73 can help shape cellular responses to extracellular ATP. In a previous study, we demonstrated that coupled CD39 and CD73 activity within synapse-like junctions is strongly controlled by the enzymes' co-localization, their surface charge densities, and the electrostatic potential of the surrounding cell membranes. In this study, we demonstrate that crowders within synaptic junctions, which can include globular proteins like cytokines and membrane-bound proteins, impact coupled CD39 and CD73 ectonucleotidase activity and, in turn, the availability of intrasynapse ATP. Specifically, we developed a spatially explicit, reaction-diffusion model for the coupled conversion of ATP → AMP and AMP → adenosine in a model synaptic junction with crowders that is solved via the finite element method. Our modeling results suggest that the association rate for ATP to CD39 is strongly influenced by the density of intrasynaptic protein crowders, as increasing crowder density generally suppressed ATP association kinetics. Much of this suppression can be rationalized based on a loss of configurational entropy. The surface charges of crowders can further influence the association rate, with the surprising result that favorable crowder-nucleotide electrostatic interactions can yield CD39 association rates that are faster than crowder-free configurations. However, attractive crowder-nucleotide interactions decrease the rate and efficiency of adenosine production, which in turn increases the availability of ATP and AMP within the synapse relative to crowder-free configurations. These findings highlight how CD39 and CD73 ectonucleotidase activity, electrostatics, and crowding within synapses influence the availability of nucleotides for intercellular communication.

Project description:BackgroundIn salivary gland carcinomas (SGC), there is only a small fraction of entities that appears to profit from immune checkpoint inhibition (ICI). Recent findings connected the activation of adenosine-signaling with a tolerogenic microenvironment. Therefore, the inhibition of adenosine pathway markers (CD39 and/or CD73) can augment ICI and/or display a novel immunotherapeutic strategy beyond ICI. Here, we assessed the immuno-histochemical expression of CD39 and CD73 across a wide spectrum of SGCs.MethodsIn total, 114 patients with SGCs consecutively diagnosed between 2001 and 2021 were assessed for clinicopathological baseline characteristics and underwent confirmatory histopathological review. Immunohistochemical expression levels of CD39 and CD73 were assessed by applying the tumor proportion score (TPS) and the immune proportional score (IPS) comparable to PD-L1 expression analysis in routine clinical practice. Additionally, findings were correlated with PD-L1 expression levels.ResultsThe median age was 60.6 and 51.8% patients were female. The cohort covered a spectrum of eight distinct entities. Advanced-stage disease (UICC/AJCC III/IVA-IVC) at initial diagnosis was present in the majority of patients (64/114). Immunohistochemical staining revealed positivity for CD39 and CD73 in 48.2% and 21.1% on tumor cells (TPS ≥ 1%) as well as 46.4% and 42.9% within the immune cell infiltrate (IPS ≥ 1%), respectively. Further comparative analyses revealed immune-cold entities such adenoid cystic carcinoma (AdCC), immune-hot tumors such as adenocarcinoma, not otherwise specified (AC (NOS)) and entities with intermediate immunologic features such as acinic cell carcinoma (ACC).ConclusionCurrent results indicate entity-specific adenosine signaling signatures. These findings suggest that the adenosine pathway plays a decisive role in tumor immunity among the major spectrum of SGCs. Targeting the adenosine pathway might pose a promising therapeutic option for selected entities.

Dataset Information

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.

Publications

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets