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
Notes: --- - "Cited By (since 1996): 54" - "Export Date: 17 November 2011" - "CODEN: NAMEF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Glenn Heller
    387 Heller
  2. Renier J Brentjens
    281 Brentjens
  3. Vladimir Ponomarev
    118 Ponomarev
  4. Alex Hongsheng Chang
    9 Chang
  5. Michel W J Sadelain
    560 Sadelain