Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

Abstract

To enlighten interactions between autologous, allogeneic or T-cells from patients after stem cell transplantation with leukaemia-derived-dendritic-cells containing dendritic cells or blast containing mononuclear cells (n ¼ 21, respectively), we determined cytokine-concentrations (interleukin 2, 4, 6, 10, tumor-necrosis-factor-a, interferon-c) in supernatants of mixed-lymphocyte-culture and in serum (n ¼ 16) of 20 patients with acute myeloid leukaemia and three patients with myelodysplastic syndromes by cytometric-bead-assay. We correlated our data with lytic capabilities of stimulated T-cells in a fluorolysis-assay and clinical data: Dendritic-cell-/mononuclear-cell-stimulation of T-cells resulted in increased cytokine-levels in culture-medium compared to serum. There were no significant differences between cytokine-patterns of cases with/without lytic T-cell-activity, response to immunotherapy (stem cell transplantation/donor-lymphocyte-infusion) or graft-versus-host-disease. However, some predictive cytokine-cut-off-values for antileukaemic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease could be defined. Cytokine-profiles alone, without functional assays, are no useful tool to predict antileukaemic T-cell-function, although they can indicate lytic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease. ARTICLE HISTORY

Role of Interferon (IFN)α in “Cocktails” for the Generation of (Leukemia-derived) Dendritic Cells (DCleu) From Blasts in Blood From Patients (pts) With Acute Myeloid Leukemia (AML) and the Induction of Antileukemic Reactions

“…Compared to "WB-control" the addition of any DC-generating method improved the average release of IFN-γ and MCP-1-pointing to an improved cytokine release profile. We assume, that patients' treatment with immunomodulatory substances change and improve the cytokine release profile, which could contribute for patients' improved response to immunotherapy as postulated by other authors 17,97,98 . Multifactorial analyses (including also cytokine -and chemokine -releaseprofiles, composition of cells of the adaptive and innate immune system) have to be performed to further illuminate these findings in correlation with antileukemic activity.…”

PGE1-Containing Protocols Generate Mature (Leukemia-Derived) Dendritic Cells Directly from Leukemic Whole Blood

“…The fact that significantly more DC/DC leu could be generated with Kit M, Kit K, and Kit I when compared to control without added response modifiers points to the fact that the combination of two response modifiers is necessary to generate DCs and DC leu in sufficient amounts directly from leukemic WB: the induction of hematopoietic differentiation is induced by GM-CSF, danger signaling, and/or maturation signaling of DC/DC leu is caused by PGE 1 , PGE 2 , or Picibanil. When compared to PBMC—cultures, response modifiers, such as IL-4 and other/unknown cytokines, are physiological components of the microenvironment in WB, and therefore they have not to be added or included in DC/DC leu -generating protocols [35]. The average amounts of generated DCs (including DC leu subgroups) were comparable with all three Kits, although amounts of matured DCs were significantly higher after WB-treatment with the PGE 1 -containing Kit M as compared to the PGE 2 -containing Kit K. This finding might also be explained by the different mode of action of PGE 1 and PGE 2 on EP receptors with different down streaming effects [61].…”

“…Monocyte chemotactic protein 1 (MCP-1, also known as CC-chemokine ligand 2, CCL-2) is an inflammatory cytokine, with antitumor activity [31]. Interleukin 17A (IL17-A) is classified as an anti-tumor response related cytokine and Interleukin 10 (IL-10) is characterized as an anti-inflammatory cytokine [32,33,34,35].…”

Research progress on dendritic cell vaccines in cancer immunotherapy

“…Different regulatory mechanisms of in vivo-induced DCs against leukemic cells have been proposed, i.e., regulatory T cells (Tregs), regulatory cytokines (e.g., IL-10) and exosomes [ 56 , 57 , 68 , 69 ] (Figs. 2 , 3 ).…”