Human acute myeloblastic leukemia cells differentiatein vitro into mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias

Abstract

An immune response is involved in the control of leukemias as demonstrated by allogeneic bone marrow transplantation, by the eradication of residual leukemic cells by cytotoxic T cells and finally by the identification of tumor antigens which are recognized by effector T cells. Dendritic cells (DC) are professional antigen‐presenting cells (APC) able to present antigens in the context of co‐stimulatory signals necessary for T cell activation. Although tumor cells may express tumor antigens, they are usually unable to elicit an immune response since they are devoid of co‐stimulatory capacities. To overcome this problem, engineering tumors to provide APC function could potentially result in polyvalent immunization to multiple tumor antigens. We have tested the differentiation of AML‐5 (monoblastic, promonocytic and monocytic) leukemia cells and demonstrated that eight out of the ten fresh human acute myeloid leukemia populations tested can differentiate in vitro into bona fide APC. Leukemic cells acquire in vitro DC morphology, mature DC markers such as CD83, the up‐regulation of MHC and co‐stimulatory molecules and the ability to produce IL‐12 upon maturation, while retaining their characteristic caryotypic abnormalities. However, we could not obtain an immature DC phenotype. They also acquire the ability to induce the differentiation of allogeneic naive cord blood CD4 and CD8 T cells as well as resting autologous cytotoxic T cells. These results demonstrate that some tumor cells acquire APC phenotype and functions and can thereby induce a potent autologous immune response that will be a valuable tool for detection of new tumor antigens and for in vivo immunization.