Treatment of Leukemic Blood Samples with Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Is Associated with Reduced Frequencies of Tolerogenic Dendritic Cells and Increased Cytotoxicity Against Autologous Blasts.

内容摘要

Background: Acute myeloid leukemia (AML) is characterized by reduced antileukemic effector cells and increased immunosuppressive cell populations. Leukemia-derived dendritic cells (DCleu), generated from 18 leukemic whole blood (WB) ex vivo using 'Kit-M' (clinically approved: GM-CSF + PGE1), lead to improved cytotoxicity against autologous blasts after mixed lymphocyte culture (MLC) with patients' T-cells. Methods: We studied Kit-M-mediated effects on frequencies of tolerogenic, immunosuppressive DC (DCtol) and correlated findings with ex vivo-achieved antileukemic effects (increased intracellular IFNγ production/degranulation, blast lysis) and patients' clinical characteristics. Results: We show significantly decreased frequencies of DCtol (and increased frequencies of mature DCleu) without induced blast proliferation in Kit-M treated vs. untreated WB samples. After T-cell-enriched MLC with Kit-M pretreated vs. not pretreated, WB frequencies of regulatory (CD152+ T-cells) were significantly decreased, while 'activated' (IFNγ+, degranulating) non-naive, proliferating, memory, CD154+) T-cells, as well as NK and CIK-cells were (significantly) increased. We found a (significant) positive correlation of achieved improved blast lysis, frequencies of DCleu and 'activated' (IFNγ+/degranulating) T- or NK/CIK cells, and a (significant) negative correlation with frequencies of DCtol and regulatory (CD152+ T-cells). Kit-M treatment of leukemic WB increases DCleu and decreases DCtol, correlating with improved immune reactions/improved cytotoxicity against autologous blasts, and downregulated suppressive T-cells in samples before or after MLC. Conclusions: These findings demonstrate the potential of Kit-M (using clinically approved drug compositions) to treat AML patients to potentially overcome the immunosuppressive tumor microenvironment, leading to improved antileukemic responses-thereby stabilizing remission of the disease in AML patients.