This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friese, M. A. Articles by Weller, M. Search for Related Content PubMed PubMed Citation Articles by Friese, M. A. Articles by Weller, M.

MICA/NKG2D-Mediated Immunogene Therapy of Experimental Gliomas

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), 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.

This article has been cited by other articles:

				C. Germain, E. Campigna, I. Salhi, S. Morisseau, I. Navarro-Teulon, J.-P. Mach, A. Pelegrin, and B. Robert Redirecting NK cells mediated tumor cell lysis by a new recombinant bifunctional protein Protein Eng. Des. Sel., November 1, 2008; 21(11): 665 - 672. [Abstract] [Full Text] [PDF]

				M. B. Fuertes, M. V. Girart, L. L. Molinero, C. I. Domaica, L. E. Rossi, M. M. Barrio, J. Mordoh, G. A. Rabinovich, and N. W. Zwirner Intracellular Retention of the NKG2D Ligand MHC Class I Chain-Related Gene A in Human Melanomas Confers Immune Privilege and Prevents NK Cell-Mediated Cytotoxicity J. Immunol., April 1, 2008; 180(7): 4606 - 4614. [Abstract] [Full Text] [PDF]

				L. Elsner, V. Muppala, M. Gehrmann, J. Lozano, D. Malzahn, H. Bickeboller, E. Brunner, M. Zientkowska, T. Herrmann, L. Walter, et al. The Heat Shock Protein HSP70 Promotes Mouse NK Cell Activity against Tumors That Express Inducible NKG2D Ligands J. Immunol., October 15, 2007; 179(8): 5523 - 5533. [Abstract] [Full Text] [PDF]

				P. Tomasec, E. C. Y. Wang, V. Groh, T. Spies, B. P. McSharry, R. J. Aicheler, R. J. Stanton, and G. W. G. Wilkinson Adenovirus vector delivery stimulates natural killer cell recognition J. Gen. Virol., April 1, 2007; 88(4): 1103 - 1108. [Abstract] [Full Text] [PDF]

				S. Heckl and U. Vogel Nuclear Trafficking of a Gadolinium Conjugate in Nude Mice Xenografted with Human LN-229 Glioma J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 657 - 662. [Abstract] [Full Text] [PDF]

				G. Eisele, J. Wischhusen, M. Mittelbronn, R. Meyermann, I. Waldhauer, A. Steinle, M. Weller, and M. A. Friese TGF-{beta} and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells Brain, September 1, 2006; 129(9): 2416 - 2425. [Abstract] [Full Text] [PDF]

				C. L. Sutherland, B. Rabinovich, N. J. Chalupny, P. Brawand, R. Miller, and D. Cosman ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15 Blood, August 15, 2006; 108(4): 1313 - 1319. [Abstract] [Full Text] [PDF]

				P. Roth, S. Aulwurm, I. Gekel, D. Beier, R. G. Sperry, M. Mittelbronn, R. Meyermann, K. D. Beaman, M. Weller, and J. Wischhusen Regeneration and tolerance factor: a novel mediator of glioblastoma-associated immunosuppression. Cancer Res., April 1, 2006; 66(7): 3852 - 3858. [Abstract] [Full Text] [PDF]

				E. P. von Strandmann, H. P. Hansen, K. S. Reiners, R. Schnell, P. Borchmann, S. Merkert, V. R. Simhadri, A. Draube, M. Reiser, I. Purr, et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo Blood, March 1, 2006; 107(5): 1955 - 1962. [Abstract] [Full Text] [PDF]

				R. M. Prins, N. Craft, K. W. Bruhn, H. Khan-Farooqi, R. C. Koya, R. Stripecke, J. F. Miller, and L. M. Liau The TLR-7 Agonist, Imiquimod, Enhances Dendritic Cell Survival and Promotes Tumor Antigen-Specific T Cell Priming: Relation to Central Nervous System Antitumor Immunity J. Immunol., January 1, 2006; 176(1): 157 - 164. [Abstract] [Full Text] [PDF]

				C. Germain, C. Larbouret, V. Cesson, A. Donda, W. Held, J.-P. Mach, A. Pelegrin, and B. Robert MHC Class I-Related Chain A Conjugated to Antitumor Antibodies Can Sensitize Tumor Cells to Specific Lysis by Natural Killer Cells Clin. Cancer Res., October 15, 2005; 11(20): 7516 - 7522. [Abstract] [Full Text] [PDF]

				L. M. Liau, R. M. Prins, S. M. Kiertscher, S. K. Odesa, T. J. Kremen, A. J. Giovannone, J.-W. Lin, D. J. Chute, P. S. Mischel, T. F. Cloughesy, et al. Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment Clin. Cancer Res., August 1, 2005; 11(15): 5515 - 5525. [Abstract] [Full Text] [PDF]

				E. K. Hellums, J. M. Markert, J. N. Parker, B. He, B. Perbal, B. Roizman, R. J. Whitley, C. P. Langford, S. Bharara, and G. Y. Gillespie Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model Neuro-oncol, July 1, 2005; 7(3): 213 - 224. [Abstract] [PDF]

				M. A. Friese, J. Wischhusen, W. Wick, M. Weiler, G. Eisele, A. Steinle, and M. Weller RNA Interference Targeting Transforming Growth Factor-{beta} Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo Cancer Res., October 15, 2004; 64(20): 7596 - 7603. [Abstract] [Full Text] [PDF]