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. The aim of this study was to determine whether chimeric NK receptor bearing T cells would directly kill tumor cells and lead to induction of host immunity against tumors. Chimeric NK receptors were produced by linking NKG2D or Dap10 to the cytoplasmic portion of the CD3ζ chain. Our results showed that chNKG2D-bearing T cells responded to NKG2D ligand-bearing tumor cells (RMA/Rae-1β, EG7) but not to wildtype tumor cells (RMA). This response was dependent upon ligand expression on the target cells but not on expression of MHC molecules, and the response could be blocked by anti-NKG2D antibodies. These T cells produced large amounts of Th1 cytokines and proinflamatory chemokines and killed ligand-expressing tumor cells. Adoptive transfer of chNKG2D-bearing T cells inhibited RMA/Rae-1β tumor growth in vivo. Moreover, mice that had remained tumor-free were resistant to subsequent challenge with the wildtype RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Adoptive transfer of chNKG2D-bearing T cells prevented growth of RMA/Rae1β tumor cells in vivo in B6 and B6.Rag1-/- mice indicating that host T and B cells were not required for the anti-tumor effect. However, only B6 mice were protected from a subsequent challenge with RMA tumor cells, suggesting that development of resistance to RMA tumor cells was dependent upon host lymphocytes and likely due to host T cells. Taken together, our findings indicate that modification of T cells with chimeric NKG2D receptors represents a promising approach for immunotherapy against cancer.

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