title: 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.
abstract: 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.
authors.affiliation: Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, Japan.
authors.forename: Sharif Uddin
authors.initials: SU
authors.lastname: Ahmed
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oshikawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tano
authors.forename: Akiko
authors.initials: A
authors.lastname: Sasai
authors.forename: Shin
authors.initials: S
authors.lastname: Kan
authors.forename: Tokafumi
authors.initials: T
authors.lastname: Hiroshima
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohue
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Moriya
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ryoma
authors.forename: Motoo
authors.initials: M
authors.lastname: Saito
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Sato
mesh_terms: 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
chemical_list: 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