Tumor lysate and IL-18 loaded dendritic cells elicits Th1 response, tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma.
In this study, we demonstrate that tumor lysate-loaded dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumor cells in patients with malignant glioma. CTL from three of five patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts and were variably cytotoxic against the LAK-sensitive cell line Daudi. Also, DCs pulsed normal brain lysate failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two of five patients CD8+ T cells expressed a modest cytotoxicity against autologous glioma cells. CD8+ T cells isolated during these ineffective primings secreted large amounts of IL-10, less amounts of IFN-gamma as detected by ELISA, Type 2 bias in the CD8+ T cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor lysate-loaded DC can be an effective tool in inducing glioma-specific CD8+ CTL able to kill autologous glioma cells in vitro. However, high levels of tumor specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. Moreover, cytotoxic responses were augmented by transfecting DC with the gene for IL-18. For all five patients, CD8+T cells treated with IL18 transfected DC produced Th1 response. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs loaded with total tumor lysate and IL-18 may represent a method for inducing Th1 immunoresponses against the entire repertoire of glioma antigens.
Yamanaka
Ryuya
R
Department of Neurosurgery, Brain Research Institute, Niigata University, Asahimachi-dori 1-757, Niigata City, 951-8585, Japan. ryaman@bri.niigata-u.ac.jp
Honma
Junpei
J
Tsuchiya
Naoto
N
Yajima
Naoki
N
Kobayashi
Tsutomu
T
Tanaka
Ryuichi
R
D000368:Aged; D001932:Brain Neoplasms / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005805:Genes, MHC Class I / Q000276:immunology; D005910:Glioma / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D020382:Interleukin-18 / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D020382:Interleukin-18