Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor beta-insensitive CD8+ T cells

Abstract

Purpose: 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.

Experimental design: 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.

Conclusion: 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.