title: Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor beta-insensitive CD8+ T cells.
abstract: 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.
authors.affiliation: Department of Urology, Xijing Hospital, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Longxin
authors.initials: L
authors.lastname: Wang
authors.forename: Weihong
authors.initials: W
authors.lastname: Wen
authors.forename: Jianlin
authors.initials: J
authors.lastname: Yuan
authors.forename: Brian
authors.initials: B
authors.lastname: Helfand
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Changhong
authors.initials: C
authors.lastname: Shi
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Jia
authors.initials: J
authors.lastname: Zheng
authors.forename: Fuli
authors.initials: F
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Lili
authors.initials: L
authors.lastname: Liang
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhou
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Chen
authors.forename: Yinglu
authors.initials: Y
authors.lastname: Guo
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Weijun
authors.initials: W
authors.lastname: Qin
mesh_terms: 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
chemical_list: D016212:Transforming Growth Factor beta; D007371:Interferon-gamma