Immunotherapy for Human Renal Cell Carcinoma by Adoptive Transfer of Autologous Transforming Growth Factor β–Insensitive CD8+ T Cells

Abstract

Purpose: Transforming growth factor-β (TGF-β) 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-β-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-β insensitive by dominant-negative TGF-β type II receptor. In addition, human RCC cell lines were generated using patients' tumor cells injected into SCID/beige mice. Renal cell carcinoma (RCC) is the most common solid tumor of the kidney in adults. It has previously been reported that the overproduction of TGF-β by RCC cells may lead to tumor evasion from the host immune surveillance and subsequent tumor progression (1-4). Similarly, inhibition of transforming growth factor-βTGF-β signaling using a dominant-negative TGF-β type II receptor construct (TβRIIDN) generates an immune response capable of eradicating tumors in mice challenged with live tumor cells (5).We have previously shown that murine CD8 + T cells that are rendered insensitive to TGF-β could activate the antitumor immune response cycle in prostate cancer and subsequently eradicate lung metastases (6, 7). Moreover, inhibition of TGF-β signaling in DC also enhanced the efficacy of 9). Although such TGF-β inhibition strategies are promising therapeutic approaches,

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