title: Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor.
abstract: To create more effective T cells against human tumors, we have designed a strategy to allow T cells to recognize tumor cells using natural killer (NK) cell receptors but retain the effector responses of T lymphocytes. NKG2D is an activating cell surface receptor expressed on NK cells and on some T-cell subsets. Its ligands are primarily expressed on tumor cells. We have shown that by linking mouse NKG2D to the CD3zeta chain, it was possible to generate a chimeric NKG2D (chNKG2D) receptor that allowed activation of murine T cells on engagement with NKG2D ligand-positive tumor cells leading to antitumor responses in mice. In this study, a human version of the chNKG2D receptor was expressed on primary human T cells, and antitumor responses were determined. Human peripheral blood mononuclear cell-derived T cells were retrovirally transduced with a human chNKG2D receptor gene. These chNKG2D-bearing human T cells responded to NKG2D ligand-positive tumor cells by producing T-helper 1 cytokines, proinflammatory chemokines, and significant cellular cytotoxicity. This response could be blocked by anti-NKG2D antibodies, and it was dependent on NKG2D ligand expression on the target cells but not on expression of MHC molecules. In addition, the activity of chNKG2D-bearing T cells remained unimpaired after exposure to a soluble NKG2D ligand, soluble MICA, at concentrations as high as 1.5 mug/mL. These data indicate the feasibility of using chNKG2D receptors in primary human T cells and suggest that this approach may be a promising means for cancer immunotherapy.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Amorette
authors.initials: A
authors.lastname: Barber
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D020298:U937 Cells
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins