The Journal of Experimental Medicine
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Published online 9 February 2004 doi:10.1084/jem.20031457
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 437-448
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Induction of Tumor-specific T Cell Immunity by Anti-DR5 Antibody Therapy

Kazuyoshi Takeda1, Noriko Yamaguchi1, Hisaya Akiba1, Yuko Kojima2, Yoshihiro Hayakawa3, Jane E. Tanner3, Thomas J. Sayers4, Naoko Seki5, Ko Okumura1, Hideo Yagita1, and Mark J. Smyth3

1 Department of Immunology, Central Laboratory of Medical Science, Juntendo University School of Medicine, Tokyo 113-8421, Japan
2 Division of Pathology, Central Laboratory of Medical Science, Juntendo University School of Medicine, Tokyo 113-8421, Japan
3 Cancer Immunology Program, Peter MacCallum Cancer Centre, 8006 Victoria, Australia
4 Basic Research Program, SAIC-Frederick Inc.
5 Laboratory of Experimental Immunology, National Cancer Institute Frederick, Frederick, MD 21702

Address correspondence to Kazuyoshi Takeda, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan. Phone: 81-3-3818-9284; Fax: 81-3-3813-0421; email: ktakeda{at}med.juntendo.ac.jp

Because tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor–expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

Key Words: apoptosis • macrophage • NK cells • CTL • TRAIL

The online version of this article contains supplemental material.

Abbreviations used in this paper: ADCC, antibody-dependent cellular cytotoxicity; ALT, alanine aminotransferase; ASGM1, asialo-GM1; AST, aspartate aminotransferase; CMA, concanamycin A; FLIP, FLICE inhibitory protein; H/E, hematoxylin/eosin; TRAIL, TNF-related apoptosis-inducing ligand.


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