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Review
. 2023 Mar 2;22(1):44.
doi: 10.1186/s12943-023-01733-x.

CD39/CD73/A2AR pathway and cancer immunotherapy

Chenglai Xia  1   2 , Shuanghong Yin  3   4 , Kenneth K W To  5 , Liwu Fu  6
Affiliations
Review

CD39/CD73/A2AR pathway and cancer immunotherapy

Chenglai Xia et al. Mol Cancer. .

Abstract

Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated.

Keywords: A2AR; Adenosine receptor; CD39; CD73; Cancer immunotherapy; Immunosuppressive tumor microenvironment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The two ectonucleotidases CD39 and CD73 control the metabolic fate of ATP and adenosine in the extracellular environment. Extracellular ATP is converted into its metabolites ADP and AMP sequentially by CD39, which is then further metabolized to adenosine by CD73. Activated CD39/CD73/A2AR signaling within the TME will suppress the function of antitumor immune cells (T cells, B cells, NK cells, and DCs) but promote the activity of the regulatory immune cells (MDSCs and Tregs), thus giving rise to a immunosuppressive TME. Notes: TME: tumor microenvironment; NK: natural killer; DCs: dendritic cells; MDSC: myeloid-derived suppressor cells; Treg: regulatory T cells; Th17: T helper 17 cells
Fig. 2
Fig. 2
Gene-expression landscape of the three major components (CD39, CD73 and A2AR) in the adenosine signaling pathway in various solid cancer types. The Cancer Genome Altas (TCGA) analysis RNA-sequencing (RNA-seq) data of ENTPD1(A), NT5E (B) and ADORA2A (C), encoding the proteins CD39, CD73, A2AR, respectively, in human cancers. Notes: LUAD: lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; PRAD: Prostate; HNSC: Head and Neck squamous cell; KIRC: Kidney renal clear cell carcinoma; UCEC: Uterinecorps Endometrial carcinoma; PCPG: Pheochromocytoma; LIHC: Liver hepatocellular carcinoma; COAD: Colon adenocarcinoma; READ: Rectum adenocarcinoma; PAAD: Pancreatic adenocarcinoma; BLCA: Bladder Urothelial Carcinoma; CESC: Cervical squamous cell carcinoma; CHOL: Cholangiocarcinoma; ESCA: Esophageal carcinoma; KICH: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; STAD: Stomach adenocarcinoma; THYM: Thyroid carcinoma; THCA: Thyroid carcinoma; BRCA: Breast invasive carcinoma; GBM: Glioblastoma multiforme. N = normal tissue; T = tumor specimen
See this image and copyright information in PMC

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