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

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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