Toll-like Receptor Signaling in Anti-Cancer Immunity

J Med Invest. 2003 Feb;50(1-2):9-24.

Abstract

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.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Adjuvants, Immunologic / therapeutic use
  • Animals
  • Antigens, Surface / physiology
  • CpG Islands / immunology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Dendritic Cells / immunology
  • Drosophila Proteins*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • Models, Immunological
  • Mouth Neoplasms / therapy
  • Mycobacterium bovis / immunology
  • Neoplasms / immunology*
  • Neoplasms, Experimental / therapy
  • Picibanil / pharmacology
  • Picibanil / therapeutic use
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 6
  • Toll-Like Receptor 9
  • Toll-Like Receptors

Substances

  • Adjuvants, Immunologic
  • Antigens, Surface
  • Cytokines
  • DNA-Binding Proteins
  • Drosophila Proteins
  • LY96 protein, human
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • TLR2 protein, human
  • TLR4 protein, human
  • TLR6 protein, human
  • TLR9 protein, human
  • Tlr6 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 6
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Picibanil
  • Interferon-gamma