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      T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection.

      Nature medicine

      metabolism, 4-1BB Ligand, T-Lymphocytes, Retroviridae, Protein Binding, immunology, Neoplasms, Microscopy, Confocal, Mice, SCID, Mice, Immune System, Humans, Cell Line, Tumor, Antigens, CD80, Antigen-Presenting Cells, Animals, Adoptive Transfer

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          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.

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          Author and article information

          Journal
          18026115
          10.1038/nm1676

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