Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways.

Abstract

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-gamma in response to RMA but not to other tumors in vitro, indicating immunity against RMA tumor antigens. ChNKG2D T cell-derived IFN-gamma 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.

• Authors: Tong Zhang, Amorette Barber, Charles L Sentman
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 22 Pg. 11029-36 (Nov 15 2007) ISSN: 1538-7445 [Electronic] United States
• PMID: 18006849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• KLRK1 protein, human
• Klrk1 protein, mouse
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Immunologic
• Receptors, Natural Killer Cell
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Interferon-gamma
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cytokines (metabolism)
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Humans
• Interferon-gamma (metabolism)
• Lymph Nodes (metabolism)
• Lymphoma, T-Cell (metabolism, therapy)
• Mice
• Mice, Inbred C57BL
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Immunologic (metabolism)
• Receptors, Natural Killer Cell
• Spleen (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Treatment Outcome