T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection Journal Article
| Authors: | Stephan, M. T.; Ponomarev, V.; Brentjens, R. J.; Chang, A. H.; Dobrenkov, K. V.; Heller, G.; Sadelain, M. |
| Article Title: | T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection |
| 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. © 2007 Nature Publishing Group. |
| Keywords: | controlled study; human cell; neoplasms; antigen expression; t lymphocyte; t-lymphocytes; animals; mice; mus; immune system; microscopy, confocal; protein binding; mice, scid; cell line, tumor; tumor cell; cell isolation; adoptive transfer; immune deficiency; tumor rejection; ligand binding; antigen-presenting cells; b7 antigen; retroviridae; 4-1bb ligand; antigens, cd80; cd137 ligand; self stimulation |
| Journal Title: | Nature Medicine |
| Volume: | 13 |
| Issue: | 12 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2007-12-01 |
| Start Page: | 1440 |
| End Page: | 1449 |
| Language: | English |
| DOI: | 10.1038/nm1676 |
| PUBMED: | 18026115 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 54" - "Export Date: 17 November 2011" - "CODEN: NAMEF" - "Source: Scopus" |
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