Antigen-Specific T-Cell Response from Dendritic Cell Vaccination Using Cancer Stem-Like Cell-Associated Antigens

Authors


  • Author contributions: Q.X.: concept and design; culture and characterization of human CSCs; human dendritic cell characterization; rat DC vaccination model and animal experiments; writing the manuscript; G.L.: human CSC expression of TAA, IFN-γ assays, tetramer assays, data analysis; X.Y.: human dendritic cell endocytosis, and supporting roles in tissue culture and rat DC vaccination model and animal experiments; M.X.: PCR and FACS experiments with G.L.; H.W.: human DC culture and antigen loading; J.J.: supporting DC culture and genotyping; B.K.: assisting with animal experiments; K.L.B.: financial support and material; J.S.Y.: concept and design, advisor and supervising role, cowriting. Q.X. and G.L. contributed equally to this work.

  • First published online in STEM CELLS EXPRESS April 23, 2009.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with current treatment remaining palliative. Immunotherapies harness the body's own immune system to target cancers and could overcome the limitations of conventional treatments. One active immunotherapy strategy uses dendritic cell (DC)-based vaccination to initiate T-cell-mediated antitumor immunity. It has been proposed that cancer stem-like cells (CSCs) may play a key role in cancer initiation, progression, and resistance to current treatments. However, whether using human CSC antigens may improve the antitumor effect of DC vaccination against human cancer is unclear. In this study, we explored the suitability of CSCs as sources of antigens for DC vaccination again human GBM, with the aim of achieving CSC-targeting and enhanced antitumor immunity. We found that CSCs express high levels of tumor-associated antigens as well as major histocompatibility complex molecules. Furthermore, DC vaccination using CSC antigens elicited antigen-specific T-cell responses against CSCs. DC vaccination-induced interferon-γ production is positively correlated with the number of antigen-specific T cells generated. Finally, using a 9L CSC brain tumor model, we demonstrate that vaccination with DCs loaded with 9L CSCs, but not daughter cells or conventionally cultured 9L cells, induced cytotoxic T lymphocytes (CTLs) against CSCs, and prolonged survival in animals bearing 9L CSC tumors. Understanding how immunization with CSCs generates superior antitumor immunity may accelerate development of CSC-specific immunotherapies and cancer vaccines. STEM CELLS 2009;27:1734–1740

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