CD73: a potent suppressor of antitumor immune responses

Beavis, Paul A.; Stagg, John; Darcy, Phillip K.; Smyth, Mark J.

doi:10.1016/j.it.2012.02.009

Cited by 330 publications

(356 citation statements)

References 84 publications

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“…ATP-induced inflammation depends on innate immune P2X7 receptors, which require high concentrations of ATP for activation. However, immune activation has been reported to be suppressed by adenosine generated from the breakdown of ATP by CD73, implying a kinetic window for ATP-induced inflammation [73]. CD73 is present on the surface of tumor cells and regulatory immune cells, suggesting that tumors might be capable of converting this inflammatory stimulus into an immunosuppressive signal.…”

Section: Potential Role For Additional Innate Immune Sensorsmentioning

confidence: 99%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

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A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

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Section: Potential Role For Additional Innate Immune Sensorsmentioning

confidence: 99%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

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“…23 In order to demonstrate that the CD39 C CD73 C CD14 C cells in PE are distinct from, e.g., tumor or mesothelial cells, which are CD14 ¡ , CD73 expression on CD3 ¡ CD14 ¡ /FSC high cells (T) vs. CD3 ¡ CD14 C FSC intermediate (M) cells was studied (Fig. 1C).…”

Section: Cd73 Is Expressed On Cd14 C Cells In Mesotheliomaassociated Pementioning

confidence: 99%

Prostaglandin E₂-mediated adenosinergic effects on CD14⁺cells: Self-amplifying immunosuppression in cancer

et al. 2017

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CD39 and CD73 are surface-expressed ectonucleotidases that hydrolyze ATP in a highly regulated, serial manner into ADP, AMP and adenosine. The end product, adenosine, has both tumor-promoting and immunosuppressive effects. The aim of this study was to determine CD73 expression on immune cells in pleural effusion (PE) in order to have a better understanding of the immune environment in mesothelioma. PE-or blood-derived CD14 C cells of mesothelioma patients and healthy donors were analyzed by flow cytometry for the expression of CD39 and CD73. CD73-induction was studied by exposure of CD14 C cells to the soluble fraction of PE (sPE), while the signaling mechanism, responsible for CD73 induction, by phosphoflow cytometry and receptor-inhibition studies. We observed CD73 expression on CD14 C cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14 C cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E 2 (PGE 2 )) and adenosine. Inhibition of PGE 2 receptors or adenosine A 2 receptors blocked CD73-induction by sPE. sPE treatment triggered protein kinase A and p38 activation. However, signal-transducer and activator of transcription 3 (STAT3)-blocking led to enhanced CD73 expression, demonstrating a hitherto unknown negative control of purinergic signaling by STAT3 in CD14 C cells. TNFa production by CD73 C CD14 C cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE 2 , cAMP or adenosine on human CD14 C cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy.

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“…Activation of A2a or A2b adenosine receptors on effector leukocytes typically (but not always) drives anti-inflammatory or immunosuppressive responses (78 -80). Thus, the relative concentrations of ATP versus ADP versus AMP that dynamically accumulate in the extracellular microenvironment of apoptotic tumor cells in vivo can variously skew local immune signaling networks between pro-inflammatory versus anti-inflammatory or immunogenic versus tolerogenic settings with significant consequences on the development of immunogenic anti-tumor responses (81)(82)(83)(84)(85)(86). Moreover, most types of tumor cells per se express different cassettes of P2 purinergic or P1 adenosine receptors that can modulate cell growth, survival, and sensitivity to pro-apoptotic mediators.…”

Section: Elevated Expression Of Panx1 Channels In Leukemic Versus Normentioning

confidence: 99%

Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-independent Mechanism

Boyd-Tressler

Peñuela

Laird

et al. 2014

Journal of Biological Chemistry

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Background: Pannexin-1 channels mediate ATP efflux and are substrates for apoptotic caspases. Results: Chemotherapeutic drugs induce ATP release via caspase-dependent gating of pannexin-1 channels and a caspase/ pannexin-1-independent mechanism in leukemic lymphocytes. Conclusion: Pannexin-1 channels that release intracellular metabolites are a novel element of cancer chemotherapy. Significance: Pannexin-1 channels link tumor cell apoptosis to purinergic regulation of anti-tumor immunity.

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CD73: a potent suppressor of antitumor immune responses

Cited by 330 publications

References 84 publications

Innate immune signaling and regulation in cancer immunotherapy

Innate immune signaling and regulation in cancer immunotherapy

Prostaglandin E₂-mediated adenosinergic effects on CD14⁺cells: Self-amplifying immunosuppression in cancer

Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-independent Mechanism

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CD73: a potent suppressor of antitumor immune responses

Cited by 330 publications

References 84 publications

Innate immune signaling and regulation in cancer immunotherapy

Innate immune signaling and regulation in cancer immunotherapy

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-independent Mechanism

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Prostaglandin E₂-mediated adenosinergic effects on CD14⁺cells: Self-amplifying immunosuppression in cancer