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

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

doi:10.3389/fimmu.2017.01918

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.

Highlights

The cancer cell death induced by some chemotherapeutic agents, especially anthracyclines, such as daunorubicin (DNR), stimulates an effective antitumor T-cell immune response in solid tumors [1,2,3] and leukemias [1], including acute myeloid leukemia (AML)
We analyzed the induction of tumor-reactive CD8+ cytotoxic T cells (CTLs) in a cohort of AML patients (n = 23) undergoing combined DNR and ARA-C chemotherapy
In 15 out of 23 patients, we observed an increase of leukemia-reactive IFN-γproducing CD8+ T cells (Figure S1 in Supplementary Material) mostly belonging to effector memory (EM) and EM expressing CD45RA subsets (Figure S2 in Supplementary Material), which highly expressed the activation marker CD38 and downregulated CD28 as compared to naïve (p = 0.03) or central memory (CM) (p = 0.03) T cells

Summary

Introduction

The cancer cell death induced by some chemotherapeutic agents, especially anthracyclines, such as daunorubicin (DNR), stimulates an effective antitumor T-cell immune response in solid tumors [1,2,3] and leukemias [1], including acute myeloid leukemia (AML). Such a death process, named immunogenic cell death, is characterized by intracellular modifications as well as alterations of tumor microenvironment, which elicit antitumor immune response and may account, at least in part, for the therapeutic effect of antineoplastic drugs [4]. To our knowledge, a tolerogenic effect of ATP release from chemotherapy-treated dying tumor cells was never investigated in AML

Methods

Results

Conclusion