Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation.
A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-gamma and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4(-/-)) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4(-/-) mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4(-/-) mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, 3-18-15 Kuramoto-cho, Tokushima 770 8504, Japan.
Masato
M
Okamoto
Sachiko
S
Furuichi
Yasuhiko
Y
Nishioka
Tetsuya
T
Oshikawa
Tomoyuki
T
Tano
Sharif Uddin
SU
Ahmed
Kiyoshi
K
Takeda
Shizuo
S
Akira
Yoshiki
Y
Ryoma
Yoichiro
Y
Moriya
Motoo
M
Saito
Saburo
S
Sone
Mitsunobu
M
Sato
D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018925:Chemokines / Q000378:metabolism; D002857:Chromium / Q000378:metabolism; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D051218:Lymphocyte Antigen 96; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D010844:Picibanil / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D013291:Streptococcus / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D002857:Chromium; D010844:Picibanil; D007371:Interferon-gamma