Ocadlikova Darina, Fiordi Benedetta, Trabanelli Sara, Salvestrini Valentina, Ciciarello Marilena, Forte Dorian, Campazzi Emma, Vitali Letizia, Cipollitta Serenella C, Pegoraro Anna, Jandus Camilla, Di Virgilio Francesco, Adinolfi Elena, Cavo Michele, Curti Antonio
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli," via Massarenti 9, 40138 Bologna, Italy.
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland.
J Leukoc Biol. 2025 Apr 23;117(4). doi: 10.1093/jleuko/qiaf010.
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 (DCs), resulting in inflammasome activation (via P2X7R), DC maturation (via P2Y11R), and indoleamine-2,3-dioxygenase 1 upregulation. However, the regulation of ATP-driven Indoleamine-2,3-dioxygenase 1 expression in human DCs 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 DCs. We identified P2Y11R as being responsible for ATP-driven indoleamine-2,3-dioxygenase 1 upregulation, and noncanonical 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 DCs induce PD-1-expressing bona 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 DCs 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.
从包括肿瘤细胞在内的垂死细胞释放的细胞外ATP，通过与树突状细胞（DC）上的嘌呤能受体结合，是炎症和耐受性的关键介质，导致炎性小体激活（通过P2X7R）、DC成熟（通过P2Y11R）以及吲哚胺-2,3-双加氧酶1上调。然而，ATP驱动的人DC中吲哚胺-2,3-双加氧酶1表达的调控研究较少。在这项工作中，我们旨在研究ATP通过嘌呤能受体对吲哚胺-2,3-双加氧酶1表达的分子调控，并深入表征由表达吲哚胺-2,3-双加氧酶1的DC诱导的ATP驱动的调节性T细胞。我们确定P2Y11R负责ATP驱动的吲哚胺-2,3-双加氧酶1上调，非经典NF-κB是与通过P2Y11R的ATP依赖性吲哚胺-2,3-双加氧酶1诱导相关的分子途径。然后，我们研究了但未证实炎性小体机制通过P2X7R参与吲哚胺-2,3-双加氧酶1上调。最后，我们评估了通过ATP外切核苷酸酶即CD39和CD73及其主要产物腺苷进行的ATP分解代谢在调节吲哚胺-2,3-双加氧酶1驱动的调节性T细胞生成中的作用。我们发现ATP驱动的吲哚胺-2,3-双加氧酶1上调与CD73上调和腺苷产生相关。此外，经ATP处理的表达吲哚胺-2,3-双加氧酶1的成熟DC通过腺苷A2AR诱导表达PD-1的真正抑制性调节性T细胞。总的来说，更深入地了解通过人DC中吲哚胺-2,3-双加氧酶1调控导致调节性T细胞诱导的ATP驱动的免疫调节机制，可能对癌症患者中吲哚胺-2,3-双加氧酶1抑制剂的开发具有临床意义，特别是与免疫疗法如抗CD73或腺苷受体激动剂以及免疫原性化疗联合使用时。
