Non-canonical NF-κB signaling in dendritic cells is required for ATP-driven indoleamine 2,3-dioxygenase 1 induction through P2Y11 receptor.

Abstract

Extracellular ATP released from dying cells, including tumor cells, is a key mediator of inflammation and tolerance by binding to purinergic receptors on dendritic cells, resulting in inflammasome activation (via P2X7R), dendritic cell maturation (via P2Y11R), and Indoleamine-2,3-dioxygenase 1 upregulation. However, the regulation of ATP-driven Indoleamine-2,3-dioxygenase 1 expression in human dendritic cells has been poorly investigated. In this work we aimed to investigate the ATP-driven molecular regulation of Indoleamine-2,3-dioxygenase 1 expression via purinergic receptors and to provide an in-depth characterization of ATP-driven T regulatory cells induced by Indoleamine-2,3-dioxygenase 1-expressing dendritic cells. We identified P2Y11R as being responsible for ATP-driven Indoleamine-2,3-dioxygenase 1 upregulation, and non-canonical NF-kB as a molecular pathway associated with ATP-dependent Indoleamine-2,3-dioxygenase 1 induction through P2Y11R. Then we investigated - but did not confirm - an involvement of inflammasome machinery through P2X7R in Indoleamine-2,3-dioxygenase 1 upregulation. Finally, we evaluated the role of ATP catabolism via ATP ectonucleotidases, i.e. CD39 and CD73 and its main product adenosine, in regulating the generation of Indoleamine-2,3-dioxygenase 1-driven T regulatory cells. We found that ATP-driven Indoleamine-2,3-dioxygenase 1 upregulation is associated with CD73 upregulation and adenosine production. Additionally, ATP-treated Indoleamine-2,3-dioxygenase 1-positive mature dendritic cells induce PD-1-expressing bone fide suppressive T regulatory cells via adenosine A2AR. Collectively, a more in-depth understanding of ATP-driven immune-regulatory mechanisms through Indoleamine-2,3-dioxygenase 1 regulation in human dendritic cells leading to the induction of T regulatory cells can have clinical implications for the development of Indoleamine-2,3-dioxygenase 1 inhibitors in cancer patients, especially in combination with immunotherapy such as an anti-CD73 or adenosine receptor agonist and immunogenic chemotherapy.