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Immunology |
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire
Requests for reprints: Charles L. Sentman, Department of Microbiology and Immunology, Dartmouth Medical School, 6W Borwell Building, One Medical Center Drive, Lebanon, NH 03756. Phone: 603-650-8007; Fax: 603-650-6223; E-mail: charles.sentman{at}dartmouth.edu.
In this study, the efficacy and mechanisms of chimeric NKG2D receptor (chNKG2D)–modified T cells in eliminating NKG2D ligand–positive RMA/Rae1 lymphoma cells were evaluated. Intravenous injection of RMA/Rae1 cells led to significant tumor formation in spleens and lymph nodes within 2 weeks. Adoptive transfer of chNKG2D-modified T cells after tumor injection significantly reduced tumor burdens in both spleens and lymph nodes, and prolonged the survival of tumor-bearing mice. Multiple treatments with chNKG2D T cells resulted in long-term tumor-free survival. Moreover, these long-term survivors were resistant to rechallenge with RMA tumor cells (NKG2D ligand–negative), and their spleen and lymph node cells produced IFN-
in response to RMA but not to other tumors in vitro, indicating immunity against RMA tumor antigens. ChNKG2D T cell–derived IFN-
and granulocyte-macrophage colony–stimulating factor, but not perforin (Pfp), tumor necrosis factor–related apoptosis-inducing ligand, or Fas ligand (FasL) alone were critical for in vivo efficacy. T cells deficient in both Pfp and FasL did not kill NKG2D ligand–positive RMA cells in vitro. Adoptive transfer of Pfp–/–FasL–/– chNKG2D T cells had reduced in vivo efficacy, indicating that chNKG2D T cells used both mechanisms to attack RMA/Rae1 cells. Taken together, these results indicate that chNKG2D T-cell–mediated therapeutic effects are mediated by both cytokine-dependent and cytotoxic mechanisms in vivo. [Cancer Res 2007;67(22):11029–36]
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