Anti-tumor effect of an intratumoral administration of dendritic cells in combination with TS-1, an oral fluoropyrimidine anti-cancer drug, and OK-432, a streptococcal immunopotentiator: involvement of toll-like receptor 4.
The authors investigated the in vivo anti-tumor effect of intratumoral administration of bone marrow-derived dendritic cells (DCs) after chemotherapy using an oral fluoropyrimidine anti-cancer drug TS-1, and followed by immunotherapeutic agent OK-432, in two syngeneic tumor-bearing mouse models. Both in Meth-A fibrosarcoma-bearing BALB/c mice and in SCCVII-bearing C3H/HeN mice, 1 week of oral administration of TS-1 effected partial eradication of established tumors. Intratumoral injection of DCs and OK-432 caused only slight inhibition of the tumor growth. However, TS-1 administration followed by DCs and OK-432 resulted in a marked inhibition in the tumor growth and also contributed to a greater prolongation of survival. By the injection of DCs and OK-432 after TS-1 administration, a significant infiltration of immune cells, especially CD8+ T cells, was observed. Furthermore, the cytotoxic activities of tumor-infiltrating lymphocytes and draining lymph node cells against inoculated tumor cells were significantly increased by the therapy, while activities against nonspecific target cells were not. Cytotoxic memory T cells were also induced; the main effectors were MHC class I-restricted, CD8+ T cells. The same therapy was also applied to SCCVII-bearing C3H/HeJ mice in which the Toll-like receptor (TLR) 4 is mutated and its function impaired; no immunotherapeutic effect was observed in the TLR4-deficient mouse model. These findings suggest that the local DC therapy in combination with TS-1 and OK-432 may be a useful strategy for the treatment of solid tumors, and that TLR4 signaling is involved in the success of this therapy.
Ahmed
Sharif Uddin
SU
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, Japan.
Okamoto
Masato
M
Oshikawa
Tetsuya
T
Tano
Tomoyuki
T
Sasai
Akiko
A
Kan
Shin
S
Hiroshima
Tokafumi
T
Ohue
Hideki
H
Moriya
Yoichiro
Y
Ryoma
Yoshiki
Y
Saito
Motoo
M
Sato
Mitsunobu
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000628:therapy; D002465:Cell Movement; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D004338:Drug Combinations; D005260:Female; D005354:Fibrosarcoma / Q000628:therapy; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D008198:Lymph Nodes / Q000166:cytology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009062:Mouth Neoplasms / Q000628:therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000628:therapy*; D010094:Oxonic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010844:Picibanil / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D005641:Tegafur / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004338:Drug Combinations; D011725:Pyridines; D011956:Receptors, Cell Surface; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C079198:S 1 (combination); D005641:Tegafur; D010844:Picibanil; D010094:Oxonic Acid