Abstract
Background: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with daunorubicin (DNR) but not cytarabine (Ara-C) results in immunogenic cell death (ICD). In the clinical setting, chemotherapy including anthracyclines and Ara-C remains a gold standard for AML treatment. In the last decade, etoposide (Eto) and fludarabine (Flu) have been added to the standard treatment for AML to potentiate its therapeutic effect and have been tested in many trials. Very little data are available about the ability of these drugs to induce ICD. Methods: AML cells were treated with all four drugs. Calreticulin and heat shock protein 70/90 translocation, non-histone chromatin-binding protein high mobility group box 1 and adenosine triphosphate release were evaluated. The treated cells were pulsed into dendritic cells (DCs) and used for in vitro immunological tests. Results: Flu and Ara-C had no capacity to induce ICD-related events. Interestingly, Eto was comparable to DNR in inducing all ICD events, resulting in DC maturation. Moreover, Flu was significantly more potent in inducing suppressive T regulatory cells compared to other drugs. Conclusions: Our results indicate a novel and until now poorly investigated feature of antineoplastic drugs commonly used for AML treatment, based on their different immunogenic potential.
Highlights
Recent evidence indicated that, under certain circumstances, chemotherapy stimulates the immune system
Background: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with daunorubicin (DNR) but not cytarabine (Ara-C) results in immunogenic cell death (ICD)
In the last decade, some chemotherapeutic agents used for acute myeloid leukemia (AML) treatment, such as anthracyclines, have been shown to induce a type of cell death that can promote modifications in cancer cells, which activate the immune system against leukemia cells [1,2,3,4]
Summary
Under certain circumstances, chemotherapy stimulates the immune system. The treatment of AML cells with daunorubicin (DNR), but not cytarabine (Ara-C), results in the maturation of dendritic cells (DCs) and in the efficient cross-priming of anti-leukemia T cells [1,3,4,5,6,7] This process, immunogenic cell death (ICD), is characterized by the coordinated emission of danger-associated molecular patterns (DAMPs), including the translocation of the endoplasmic reticulum (ER) chaperones such as calreticulin (CRT) and heat shock proteins (HSPs) 70 and 90 on the cell surface, the active secretion of adenosine triphosphate (ATP), the release of high mobility group box 1 (HMGB1) from the nucleus in the extracellular milieu [8,9,10,11,12] and, the release of immunostimulatory cytokines, such as type I interferons [13,14]. We studied the immunogenic potential of Eto and Flu as compared to DNR and Ara-C
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