Chemotherapy-Induced Tumor Cell Death at the Crossroads Between Immunogenicity and Immunotolerance: Focus on Acute Myeloid Leukemia

Abstract

In solid tumors and hematological malignancies, including acute myeloid leukemia, some chemotherapeutic agents, such as anthracyclines, have proven to activate an immune response via dendritic cell-based cross-priming of anti-tumor T lymphocytes. This process, known as immunogenic cell death, is characterized by a variety of tumor cell modifications, i.e., cell surface translocation of calreticulin, extracellular release of adenosine triphosphate and pro-inflammatory factors, such as high mobility group box 1 proteins. However, in addition to with immunogenic cell death, chemotherapy is known to induce inflammatory modifications within the tumor microenvironment, which may also elicit immunosuppressive pathways. In particular, DCs may be driven to acquire tolerogenic features, such as the overexpression of indoleamine 2,3-dioxygensase 1, which may ultimately hamper anti-tumor T-cells via the induction of T regulatory cells. The aim of this review is to summarize the current knowledge about the mechanisms and effects by which chemotherapy results in both activation and suppression of anti-tumor immune response. Indeed, a better understanding of the whole process underlying chemotherapy-induced alterations of the immunological tumor microenvironment has important clinical implications to fully exploit the immunogenic potential of anti-leukemia agents and tune their application.

Keywords: T regulatory cells; acute myeloid leukemia; dendritic cells; immunogenic cell death; immunosuppression.

Figure 1

Balance between immune activation and tolerance during ICD in AML. Immunogenic chemotherapy causes the release of DAMPs (CRT, HSPs, ATP, and HMGB1) which bind to receptors on DCs as CD91, TLR4, and P2X7. DCs up-regulate maturation markers (CD80, CD86, and CD83) and produce IL-1β resulting in activation of T cells producing IFN-γ At the same time, DCs up-regulate IDO1 which is responsible for the production of kynurenines which in turn stimulate induction of Tregs producing IL-10 and inhibit effector T cells. IDO1 is expressed also on AML cells and Treg cells, thus participating to the suppressive local milleu. Immune check points receptors (ICRs) as PD-1, Tim-3, Lag-3, CD200R, and CTLA-4 can contribute to the cell composition of tumor microenvironment. In this context, IDO1 seems to play a key role in the balance between immune system activation and tolerance in AML during ICD.