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Differentiation of Human Embryonic Stem Cells into Immunostimulatory Dendritic Cells under Feeder-Free Culture Conditions

Authors' Affiliation: Department of Urology, College of Medicine, University of Florida, Gainesville, Florida

Requests for reprints: Zhen Su, Department of Urology, University of Florida, College of Medicine, Health Science Center, Box 100247, Gainesville, FL 32610. Phone: 352-273-8236; Fax: 352-273-8335; E-mail: zhen{at}urology.ufl.edu.

Purpose: The objective of this study was to develop a scalable and broadly applicable active immunotherapy approach against cancer, circumventing the limitations typically encountered with autologous vaccination strategies. We hypothesized that human embryonic stem cells (hESC) can serve as a virtually unlimited source for generating dendritic cells (DC) with potent antigen-presenting function. Here, we investigated the developmental processes and requirements for generating large numbers of mature, antigen-presenting DC from pluripotent hESC.

Experimental Design: A feeder cell-free culture system was developed to differentiate hESC into mature DC sequentially through hematopoietic and myeloid precursor stages.

Results: Using this method, we were able to yield large numbers of mature immunostimulatory DC from hESC to enable clinical investigation. Upon activation, the hESC-derived DC secreted interleukin-12p70, migrated in response to MIP-3β, and exhibited allostimulatory capacity. Most importantly, antigen-loaded, hESC-derived DC were capable of stimulating potent antigen-specific CD8⁺ T-cell responses in an HLA class I–matched semiallogeneic assay system. Moreover, HLA class II–mismatched hESC-derived DC induced a potent Th1-type cytokine response without expanding FOXP3⁺ regulatory T cells in vitro.

Conclusions: These data suggest the development of a novel active immunotherapy platform to stimulate potent T-cell immunity in patients with intractable diseases, such as cancer or viral infection.