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[Cancer Research 65, 1761-1769, March 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Adoptive Transfer of Tumor-Reactive Transforming Growth Factor-ß–Insensitive CD8+ T Cells: Eradication of Autologous Mouse Prostate Cancer

Qiang Zhang1, Ximing Yang2, Michael Pins2, Borko Javonovic3, Timothy Kuzel4, Seong-Jin Kim5, Luk Van Parijs6, Norman M. Greenberg7, Victoria Liu1, Yinglu Guo8 and Chung Lee1

Departments of 1 Urology, 2 Pathology, 3 Preventive Medicine, and 4 Medicine, Northwestern University's Feinberg School of Medicine, Chicago, Illinois; 5 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland; 6 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; 7 Fred Hutchinson Cancer Research Center, Seattle, Washington; and 8 Institute of Urology, Peking University, Beijing, China

Requests for reprints: Chung Lee, Northwestern University's Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 16-733, Chicago, IL 60611. Phone: 312-908-2004; Fax: 312-908-7572; E-mail: c-lee7{at}northwestern.edu.

Transforming growth factor (TGF)-ß is a potent immunosuppressant. Overproduction of TGF-ß by tumor cells may lead to tumor evasion from the host immune surveillance and tumor progression. The present study was conducted to develop a treatment strategy through adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-ß1 and were used as an experimental model. C57BL/6 mice were primed with irradiated TRAMP-C2 cells. CD8+ T cells were isolated from the spleen of primed animals, were expanded ex vivo, and were rendered TGF-ß insensitive by infecting with a retrovirus containing dominant-negative TGF-ß type II receptor. Results of in vitro cytotoxic assay revealed that these CD8+ T cells showed a specific and robust tumor-killing activity against TRAMP-C2 cells but were ineffective against an irrelevant tumor line, B16-F10. To determine the in vivo antitumor activity, recipient mice were challenged with a single injection of TRAMP-C2 cells for a period up to 21 days before adoptive transfer of CD8+ T cells was done. Pulmonary metastasis was either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-ß-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-ß-insensitive CD8+ T cells were able to persist in tumor-bearing hosts but declined in tumor-free animals. These results suggest that adoptive transfer of tumor-reactive TGF-ß-insensitive CD8+ T cells may warrant consideration for cancer therapy.

Key Words: TGF-ß • adoptive transfer • gene therapy • CD8+ T cell • immunosurveillance • tumor rejection




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Copyright © 2005 by the American Association for Cancer Research.