Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways.
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.
Zhang
Tong
T
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Barber
Amorette
A
Sentman
Charles L
CL
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D013154:Spleen / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016896:Treatment Outcome
D016207:Cytokines; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor