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[Cancer Research 63, 8996-9006, December 15, 2003]
© 2003 American Association for Cancer Research

Immunology

MICA/NKG2D-Mediated Immunogene Therapy of Experimental Gliomas

Manuel A. Friese1, Michael Platten1, Stefan Z. Lutz3, Ulrike Naumann1, Steffen Aulwurm1, Felix Bischof1, Hans-Jörg Bühring2, Johannes Dichgans1, Hans-Georg Rammensee3, Alexander Steinle3 and Michael Weller1

1 Departments of Neurology and
2 Hematology, Oncology, and Immunology, and
3 Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany

The failure of conventional cancer therapy renders glioblastoma an attractive target for immunotherapy. Tumor cells expressing ligands of the activating immunoreceptor NKG2D stimulate tumor immunity mediated by natural killer (NK), {gamma}{delta} T, and CD8+ T cells. We report that human glioma cells express the NKG2D ligands MICA, MICB, and members of the UL16-binding protein family constitutively. However, glioma cells resist NK cell cytolysis because of high MHC class I antigen expression. Plasmid-mediated or adenovirus-mediated overexpression of MICA in glioma cells enhances their sensitivity to NK and T-cell responses in vitro and markedly delays the growth of s.c. and intracerebral LN-229 human glioma cell xenografts in nude mice and of SMA-560 gliomas in syngeneic VMDk mice. Glioma cells forming progressive tumors after implantation of stably MICA-transfected human LN-229 cells lost MICA expression, indicating a strong selection against MICA expression in vivo. Rejection of MICA-expressing SMA-560 cells in VMDk mice resulted in protective immunity to a subsequent challenge with wild-type tumor cells. Finally, the growth of syngeneic intracerebral SMA-560 tumors is inhibited by peripheral vaccination with adenovirus-mediated, MICA-infected irradiated tumor cells, and vaccination results in immune cell activation in the NK and T-cell compartments in vivo. These data commend MICA immunogene therapy as a novel experimental treatment for human malignant gliomas.




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