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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1544-1551.
Prepublished online as a Blood First Edition Paper on May 12, 2005; DOI 10.1182/blood-2004-11-4365.
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Submitted November 16, 2004
Accepted April 15, 2005
Chimeric NK receptor-bearing T cells mediate anti-tumor immunotherapy
Tong Zhang, Bethany A Lemoi, and Charles L Sentman*
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA
* Corresponding author; email: Charles.Sentman{at}Dartmouth.edu.
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 NKG2D (chNKG2D) receptor bearing T cells will 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 CD3 chain. Our results showed that chNKG2D-bearing T cells responded to NKG2D ligand-bearing tumor cells (RMA/Rae-1 ,EG7) but not to wild-type 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-1 tumor growth. Moreover, mice that had remained tumor-free were resistant to subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Taken together, our findings indicate that modification of T cells with chimeric NKG2D receptors represents a promising approach for immunotherapy against cancer.
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