Article abstract
Nature Medicine 13, 1440 - 1449 (2007)
Published online: 18 November 2007 | doi:10.1038/nm1676
T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection
Matthias T Stephan1,2, Vladimir Ponomarev3, Renier J Brentjens1,4, Alex H Chang1, Konstantin V Dobrenkov3, Glenn Heller5 & Michel Sadelain1,2,4
Abstract
To reject tumors, T cells must overcome poor tumor immunogenicity and an adverse tumor microenvironment. Providing agonistic costimulatory signals to tumor-infiltrating T cells to augment T cell function remains a challenge for the implementation of safe and effective immunotherapy. We hypothesized that T cells overexpressing selected costimulatory ligands could serve as cellular vehicles mediating powerful, yet constrained, anatomically targeted costimulation. Here, we show that primary human T cells expressing CD80 and 4-1BB ligand (4-1BBL) vigorously respond to tumor cells lacking costimulatory ligands and provoke potent rejection of large, systemic tumors in immunodeficient mice. In addition to showing costimulation of bystander T cells (transcostimulation), we show the effect of CD80 and 4-1BBL binding to their respective receptors in the immunological synapse of isolated single cells (autocostimulation). This new strategy of endowing T cells with constitutively expressed costimulatory ligands could be extended to other ligand-receptor pairs and used to enhance any targeted adoptive transfer therapy.
- Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York 10021, USA.
- Immunology Graduate Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
- Department of Radiology, MSKCC, New York, New York 10021, USA.
- Department of Medicine, MSKCC, New York, New York 10021, USA.
- Department of Epidemiology and Biostatistics, MSKCC, New York, New York 10021, USA.
Correspondence to: Michel Sadelain1,2,4 e-mail: m-sadelain@ski.mskcc.org
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