Retrovirally transduced murine T lymphocytes expressing FasL mediate effective killing of prostate cancer cells
- 19 December 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Gene Therapy
- Vol. 16 (5), 439-452
- https://doi.org/10.1038/cgt.2008.96
Abstract
Adoptively transferred T cells possess anticancer activities partially mediated by T-cell FasL engagement of Fas tumor targets. However, antigen-induced T-cell activation and clonal expansion, which stimulates FasL activity, is often inefficient in tumors. As a gene therapy approach to overcome this obstacle, we have created oncoretroviral vectors to overexpress FasL or non-cleavable FasL (ncFasL) on murine T cells of a diverse T-cell receptor repertoire. Expression of c-FLIP was also engineered to prevent apoptosis of transduced cells. Retroviral transduction of murine T lymphocytes has historically been problematic, and we describe optimized T-cell transduction protocols involving CD3/CD28 co-stimulation of T cells, transduction on ice using concentrated oncoretrovirus, and culture with IL-15. Genetically modified T cells home to established prostate cancer tumors in vivo. Co-stimulated T cells expressing FasL, ncFasL and ncFasL/c-FLIP each mediated cytotoxicity in vitro against RM-1 and LNCaP prostate cancer cells. To evaluate the compatibility of this approach with current prostate cancer therapies, we exposed RM-1, LNCaP, and TRAMP-C1 cells to radiation, mitoxantrone, or docetaxel. Fas and H-2b expression were upregulated by these methods. We have developed a novel FasL-based immuno-gene therapy for prostate cancer that warrants further investigation given the apparent constitutive and inducible Fas pathway expression in this malignancy.Keywords
This publication has 58 references indexed in Scilit:
- T-Cell Receptor Gene Therapy of Established Tumors in a Murine Melanoma ModelJournal of Immunotherapy, 2008
- IL-2 signaling and CD4+CD25+Foxp3+ regulatory T cellsFrontiers in Bioscience-Landmark, 2008
- Fas Ligand Delivery by a Prostate-Restricted Replicative Adenovirus Enhances Safety and Antitumor EfficacyClinical Cancer Research, 2007
- Gene transfer of human TCR in primary murine T cells is improved by pseudo‐typing with amphotropic and ecotropic envelopesThe Journal of Gene Medicine, 2007
- Activation of CD95L fusion protein prodrugs by tumor-associated proteasesCell Death & Differentiation, 2006
- Cancer Regression in Patients After Transfer of Genetically Engineered LymphocytesScience, 2006
- Prolonged exposure of naïve CD8+ T cells to interleukin‐7 or interleukin‐15 stimulates proliferation without differentiation or loss of telomere lengthImmunology, 2006
- Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugsZeitschrift für Krebsforschung und Klinische Onkologie, 2003
- CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effectsBlood, 2003
- T Cell Activation Modulates Retrovirus-Mediated Gene ExpressionHuman Gene Therapy, 1998