Toll-like receptor signaling in anti-cancer immunity.
It is important to augment the anti-cancer host response in cancer treatment. Recent studies suggested that the signaling via Toll-like receptors (TLRs) which are newly identified receptor molecules recognizing many pathogens, are involved in the induction of anti-cancer immunity. Seya et al. demonstrated that maturation of dendritic cells (DCs) and cytokine induction by the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin (BCG-CWS) are induced via both TLR2 and TLR4. Akira et al. discovered a new molecule of TLR family, TLR9, recognizing unmethylated bacterial CpG-DNA, whose clinical use is expected for cancer therapy as a potent inducer of a helper T cell 1 (Th1)-type T-cell response. TLR9-deficient mice did not show any responses to CpG-DNA, including Th 1 cytokine production and maturation of DCs. We have obtained two molecules, a lipoteichoic acid-related molecule isolated from streptococcal agent OK-432, and a plant-derived 55-kDa protein that can induce Th1 response and elicit a strong anti-cancer effect in vivo and in vitro. Our basic experiments demonstrate that TLR4 signaling is intimately involved in anti-cancer immunity induced by these immunopotentiators. Our clinical examination in oral cancer patients also suggests the requirement of both TLR4 and MD-2 in the OK-432-induced anti-cancer host response. Establishment and clinical use of the methodology for human cancer therapy by utilizing TLR signaling is greatly expected.
Okamoto
Masato
M
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, Japan.
Sato
Mitsunobu
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000954:Antigens, Surface / Q000502:physiology; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D029721:Drosophila Proteins; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D018448:Models, Immunological; D009062:Mouth Neoplasms / Q000628:therapy; D009163:Mycobacterium bovis / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000628:therapy; D010844:Picibanil / Q000494:pharmacology / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D000276:Adjuvants, Immunologic; D000954:Antigens, Surface; D016207:Cytokines; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495368:TLR6 protein, human; C495371:TLR9 protein, human; C495369:Tlr6 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D010844:Picibanil; D007371:Interferon-gamma