The yin and yang functions of extracellular ATP and adenosine in tumor immunity

Abstract

Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors. eATP and ADO, like yin and yang, represent two opposite aspects from immuneactivating to immune-suppressive signals. Here we reviewed the functions of eATP and ADO in tumor immunity and attempt to block eATP hydrolysis, ADO formation and their contradictory effects in tumor models, allowing the induction of effective anti-tumor immune responses in TME. These attempts documented that therapeutic approaches targeting eATP/ADO metabolism and function may be effective methods in cancer therapy.

Plecstatin-1 induces an immunogenic cell death signature in colorectal tumour spheroids

“…71 This process is essential for inducing an ICD response, stimulating host-specific immune responses against the tumour. 71,72 Praemortem release of ATP relies on an autophagy-dependent process involving the caspase-3 mediated proteolytic activation of pannexin-1 channels. 70,73 To assess ATP release, supernatants from plecstatin-1 treated and untreated spheroids were collected and analysed by means of a luminescence assay.…”

“…The emerging evidence that purinergic signalling influences cell proliferation and migration, tumour angiogenesis as well as invasiveness and metastatic diffusion in different types of cancer has substantially increased the number of studies in the field. [71][72][73][74] It has been recently shown that P2Y 2 receptors mediate the phosphorylation of EGFR, thus promoting the proliferation and tumorigenesis of head and neck squamous cell carcinoma cell lines. 74 Furthermore, blocking P2X7 receptors has been shown to be an efficient way to prevent tumour growth in cancers where this receptor is overexpressed.…”

Osteocytes and Bone Metastasis

“…The intracellular concentration of ATP is ~3–10 mM, and the extracellular ATP (eATP) is about 10 nM. The big difference between intracellular and extracellular ATP is from active ATP degradation through ectonucleotidases in the extracellular compartment ( 93 ). The presence of eATP has been shown to inhibit the growth of pancreatic, colon, prostate, breast, liver, ovarian, colorectal, esophageal, melanoma, and leukemia ( 94 ).…”

“…Multiple studies show an anticancer action of eATP or eATP analogs by binding to P2 purinergic receptors ( 90 , 98 ). eATP is rapidly degraded to adenosine, a well-known tumorigenic factor ( 92 , 93 , 99 ). Additionally, eATP or P2 receptor agonist decreases osteoclast activity and bone resorption ( Figure 2 , step ⑤) ( 100 ), reduces the number of T regulatory lymphocytes (Tregs) ( 101 ), and prolongs the activity of T lymphocytes ( Figure 2 , step ⑥) ( 102 ).…”

“…This microenvironment also results in poor immune surveillance with high lymphocytic tolerance ( Figure 1 , steps ⑥and ⑧) ( 92 , 105 , 106 ). The main pathway leading to high extracellular adenosine levels is the hydrolysis of eATP by a family of enzymes known as ectonucleotidases, such as CD39 and CD73, which hydrolyze ATP and ADP to AMP, and AMP further to adenosine ( Figure 1 , step ⑥) ( 93 , 105 ). CD73 has been associated with a pro-metastatic phenotype in breast cancer, and CD73 knockdown leads to suppression of breast cancer cell growth, migration, and invasion both in vivo and in vitro ( 105 ).…”