Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Abstract

We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

Malignant counterpart of myeloid dendritic cell (DC) belonging to acute myelogenous leukemia (AML) exhibits a dichotomous immunoregulatory potential

“…In contrast to other AML blast-derived DCs [12][13][14], the current study indicates that DC-like leukemia already expresses some DC characteristics without the requirement of ex vivo culture in the presence of cytokines. According to the French-American-British (FAB) classification, DC-like leukemic cells may be similar to blasts of mature monocytic leukemia [M5b, defined as follows: Differentiated monocytic leukemic cells with a large cerebriform nucleus are found in a higher proportion in the PB than in the bone marrow (BM)] [17,18]; however, these cells are unique in phenotype and function.…”

“…The PBMC of some patients with acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML) with addition of cytokines can sometimes be induced to differentiate into a newly elucidated, malignant counterpart of myeloid DCs, based on phenotypic and functional characteristics, such as the ability to stimulate antigen-specific cytotoxic T cells (CTLs) [11][12][13][14][15]. As a result, these leukemic cells have been envisioned as useful therapeutic reagents for treatment in patients.…”

Cyclin B1 is commonly expressed in the cytoplasm of primary human acute myelogenous leukemia cells and serves as a leukemia‐associated antigen associated with autoantibody response in a subset of patients

“…A dendritic AML cell phenotype can be induced by in vitro culture of native AML cells in the presence of exogenous cytokines (65)(66)(67)(68). Previous detailed characterization of our in vitro model has demonstrated that these cells have a leukemic origin and their phenotype includes (56): (i) production of cytokines that support T-cell activation and drive Th1 polarization; (ii) generation of autologous, leukemia-specific and HLA-restricted CD8 + and CD4 + T-cell responses; (iii) migration from tissues to lymph nodes; (iv) amplification of antigen presentation by monocyte attraction; (v) attraction of naive ⁄ resting and activated T cells.…”

Immunological weapons against acute myeloid leukaemia

“…Several investigators have now shown that under the influence of GM-CSF and IL-4 in combination with tumour necrosis factor-a (TNF-a), and CD40L or FLT3-L, AML cells can differentiate into DC, irrespective of their FAB classification and clinical status. [79][80][81][82][83] Under these conditions, the AML-differentiated DC unlike their original blasts, express molecules typical of DC markers including CD1a, CD83, B7.1 and B7.2, CD40 and high-class I and class II. In these studies, the AML-differentiated DCs have been shown to be effective at stimulating both allogeneic and autologous T-cell proliferative responses.…”