ATP release from chemotherapy-treated dying leukemia cells Elicits an immune suppressive effect by increasing regulatory T cells and Tolerogenic dendritic cells

Mariangela Lecciso, Darina Ocadlikova, Sabina Sangaletti, Sara Trabanelli, Elena De Marchi, Elisa Orioli, Anna Pegoraro, Paola Portararo, Camilla Jandus, Andrea Bontadini, Annarita Redavid, Valentina Salvestrini, Pedro Romero, Mario P. Colombo, Francesco Di Virgilio, Michele Cavo, Elena Adinolfi, Antonio Curti

Research output: Contribution to journalArticle

Abstract

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 in vitro 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 in vivo 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.

Original languageEnglish
Article number1918
JournalFrontiers in Immunology
Volume8
Issue numberDEC
DOIs
Publication statusPublished - Dec 22 2017

Keywords

  • Acute myeloid leukemia
  • ATP
  • Chemotherapy
  • Dendritic cell
  • Immunosuppression
  • T regulatory cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Lecciso, M., Ocadlikova, D., Sangaletti, S., Trabanelli, S., De Marchi, E., Orioli, E., Pegoraro, A., Portararo, P., Jandus, C., Bontadini, A., Redavid, A., Salvestrini, V., Romero, P., Colombo, M. P., Di Virgilio, F., Cavo, M., Adinolfi, E., & Curti, A. (2017). ATP release from chemotherapy-treated dying leukemia cells Elicits an immune suppressive effect by increasing regulatory T cells and Tolerogenic dendritic cells. Frontiers in Immunology, 8(DEC), [1918]. https://doi.org/10.3389/fimmu.2017.01918