Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor beta-insensitive CD8+ T cells.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) is a potent immunosuppressor that has been associated with tumor evasion from the host immune surveillance and, thus, tumor progression. We tested a novel immunotherapy for human renal cell cancer (RCC) using a technique that involves the adoptive transfer of autologous tumor-reactive, TGF-beta-insensitive CD8(+) T cells into human RCC-challenged immunodeficient mice to identify its potent antitumor responses.


METHODS
The present study was conducted using a one-to-one adoptive transfer strategy to treat tumor-bearing severe combined immunodeficient (SCID/beige) mouse. The SCID/beige mice were humanized with peripheral blood mononuclear cells from patients with RCC (Hu-PBMC-SCID) before adoptive transfer. Autologous CD8(+) T cells were expanded ex vivo using autologous patient's dendritic cells pulsed with the tumor lysate and rendered TGF-beta insensitive by dominant-negative TGF-beta type II receptor. In addition, human RCC cell lines were generated using patients' tumor cells injected into SCID/beige mice.


RESULTS
Using flow cytometry analysis, we confirmed the expression of the tumor-reactive, TGF-beta-insensitive CD8(+) T cells were the effector CD8(+) cells (CD27(-)CDRA(+)). Adoptive transfer of autologous TGF-beta-insensitive CD8(+) T cells into tumor-bearing Hu-PBMC-SCID mice induced robust tumor-specific CTL responses in vitro, were associated with tumor apoptosis, suppressed lung metastasis, and prolonged survival times in vivo.


CONCLUSIONS
The one-to-one adoptive transfer strategy is an ideal in vivo murine model for studying the relationship between TGF-beta and immunosurveillance in RCC in vivo. Furthermore, this technique may offer the promise of a novel therapeutic option for the treatment of human patients with RCC.
Wang
Longxin
L
Department of Urology, Xijing Hospital, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
Wen
Weihong
W
Yuan
Jianlin
J
Helfand
Brian
B
Li
Yu
Y
Shi
Changhong
C
Tian
Feng
F
Zheng
Jia
J
Wang
Fuli
F
Chen
Lin
L
Liang
Lili
L
Zhou
Liqun
L
Lee
Chung
C
Chen
Zhinan
Z
Guo
Yinglu
Y
Wang
He
H
Zhang
Qiang
Q
Qin
Weijun
W
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D016212:Transforming Growth Factor beta / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D016212:Transforming Growth Factor beta; D007371:Interferon-gamma