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Research Articles: Therapeutics

Blockade of transforming growth factor-ß signaling in tumor-reactive CD8⁺ T cells activates the antitumor immune response cycle

Departments of ¹ Urology, ² Pathology, ³ Preventive Medicine, ⁴ Medicine, and ⁵ Cell and Molecular Biology, Northwestern University Feinberg School of Medicine and ⁶ Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois; ⁷ Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland; ⁸ Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁹ Institute of Urology, The First Hospital, Peking University, Beijing, China

Requests for reprints: Chung Lee, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 16-733, Chicago, IL 60611. Phone: 312-908-2004; Fax: 312-908-7275. E-mail: c-lee7{at}northwestern.edu

Transforming growth factor-ß (TGF-ß) is a potent immunosuppressant. Overproduction of TGF-ß by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-ß-insensitive CD8⁺ T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8⁺ T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8⁺ T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-ß by introducing a dominant-negative TGF-ß type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 x 10⁵) into the flank of male BALB/c-Rag1^–/– mice, tumor-reactive, TGF-ß-insensitive CD8⁺ T cells (1.5 x 10⁷) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8⁺ T cells or green fluorescent protein-empty vector–transfected tumor-reactive CD8⁺ T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-ß-insensitive CD8⁺ T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8⁺ T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology. [Mol Cancer Ther 2006;5(7):1733-43]

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Received 3/ 2/06; revised 5/10/06; accepted 5/23/06.

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