ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

• Published in: Frontiers in immunology Vol. 8; p. 1918
• Main Authors: Lecciso, Mariangela, Ocadlikova, Darina, Sangaletti, Sabina, Trabanelli, Sara, De Marchi, Elena, Orioli, Elisa, Pegoraro, Anna, Portararo, Paola, Jandus, Camilla, Bontadini, Andrea, Redavid, Annarita, Salvestrini, Valentina, Romero, Pedro, Colombo, Mario P, Di Virgilio, Francesco, Cavo, Michele, Adinolfi, Elena, Curti, Antonio
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 22.12.2017
• Subjects: acute myeloid leukemia; ATP; chemotherapy; dendritic cell; Immunology; immunosuppression; T regulatory cells; immunosuppression; acute myeloid leukemia; T regulatory cells; ATP; chemotherapy; dendritic cell
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.01918

Chemotherapy-induced immunogenic cell death can favor dendritic cell (DC) cross-priming of tumor-associated antigens for T cell activation thanks to the release of damage-associated molecular patterns, including ATP. Here, we tested the hypothesis that in acute myeloid leukemia (AML), ATP release, along with its well-known immune stimulatory effect, may also contribute to the generation of an immune suppressive microenvironment. In a cohort of AML patients, undergoing combined daunorubicin and cytarabine chemotherapy, a population of T regulatory cells (Tregs) with suppressive phenotype, expressing the immune checkpoint programmed cell death protein 1 (PD-1), was significantly increased. Moving from these results, initial data showed that daunorubicin was more effective than cytarabine in modulating DC function toward Tregs induction and such difference was correlated with the higher capacity of daunorubicin to induce ATP release from treated AML cells. DCs cultured with daunorubicin-treated AML cells upregulated indoleamine 2,3-dioxygenase 1 (IDO1), which induced anti-leukemia Tregs. These data were confirmed as daunorubicin-treated mice show an increase in extracellular ATP levels with increased number of Tregs, expressing PD-1 and IDO1 CD39 DCs. Notably, daunorubicin failed to induce Tregs and tolerogenic DCs in mice lacking the ATP receptor P2X7. Our data indicate that ATP release from chemotherapy-treated dying cells contributes to create an immune suppressive microenvironment in AML.