Streptococcal preparation OK-432 promotes the capacity of dendritic cells (DCs) to prime carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte responses induced with genetically modified DCs that express CEA.
Cancer immunotherapy using dendritic cells (DCs) adenovirally transduced with the whole tumor-associated antigen (TAA) gene is an effective approach. Streptococcal preparation OK-432 is useful for stimulating DCs in terms of maturation. In this study, we established carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes (CTLs) using in vitro stimulation with adenovirally modified human DCs that express CEA. We investigated whether OK-432 stimulation could be more effective in inducing CEA-specific CTLs compared with other typical stimuli. DCs adenovirally transduced with the CEA gene were cultured under various conditions with tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), or OK-432. A cytotoxicity assay using peripheral blood mononuclear cell (PBMC)-derived CTLs was performed in a 4 h-51Cr release assay. OK-432 stimulated immature DCs to acquire a mature phenotype and to produce significant amounts of T-helper 1 cytokines. In all groups (immature DCs, TNF-alpha/DCs, LPS/DCs, OK-432/DCs), CEA-specific CTLs were generated. OK-432-stimulated DCs (HLA-A24) induced the most potent cytotoxic activity against CEA-expressing targets (A24) but not against controls. OK-432/DCs were able to induce markedly potent CTLs specific to target cells pulsed with CEA652 peptide (HLA-A24-restricted peptide), although others failed to induce potent CTLs. In conclusion, the CTL induction protocol using adenovirally modified DCs that express CEA after maturation with OK-432 showed a potent antitumor activity against CEA-expressing target cells, and is therefore promising for clinical applications as a cancer vaccine therapy.
Ojima
Toshiyasu
T
Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimidera, Wakayama 641-8510, Japan.
Iwahashi
Makoto
M
Nakamura
Masaki
M
Matsuda
Kenji
K
Nakamori
Mikihito
M
Ueda
Kentaro
K
Naka
Teiji
T
Katsuda
Masahiro
M
Miyazawa
Motoki
M
Iida
Takeshi
T
Yamaue
Hiroki
H
D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005821:Genetic Techniques; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010844:Picibanil / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002272:Carcinoembryonic Antigen; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D010844:Picibanil; D007371:Interferon-gamma