In order to create more effective CTLs against human tumors, we have designed a strategy to allow T cells to recognize tumor cells using NK cell receptors but retain the effector responses of T lymphocytes. NKG2D is an activating cell-surface receptor expressed on natural killer (NK) cells and some T-cell subsets. Its ligands are primarily expressed on tumor cells. We have shown that by linking mouse NKG2D to the CD3 zeta chain we were able to generate a chimeric NKG2D receptor (chNKG2D) that allowed direct activation of murine T cells upon engagement with NKG2D ligand-positive tumor cells leading to anti-tumor responses in mice. In this study, a human version of the chNKG2D receptor was expressed on human T cells and anti-tumor responses determined. Human PBMC-derived T cells were retrovirally transduced with the human chNKG2D receptor gene. These chNKG2D-bearing human T cells responded to NKG2D ligand-positive tumor cells by producing T-helper 1 (Th1) cytokines, proinflammatory chemokines and significant cellular cytotoxicity. This response was dependent upon NKG2D ligand expression on the target cells but not on expression of MHC molecules, and this response was blocked by anti-NKG2D antibodies. In addition, the activity of chNKG2D-bearing T cells remained unimpaired after exposure to a soluble NKG2D ligand, soluble MICA, at a concentration as high as 150ng/ml. These data indicate the feasibility of developing chimeric NKG2D receptors on human T cells and suggest this approach may be a promising means for cancer immunotherapy.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]