Enhanced activation of human dendritic cells by inducible CD40 and Toll-like receptor-4 ligation

Cancer Res. 2007 Nov 1;67(21):10528-37. doi: 10.1158/0008-5472.CAN-07-0833.


Despite the potency of dendritic cells (DC) as antigen-presenting cells for priming adaptive immunity, DC-based cancer vaccines have been largely insufficient to effectively reduce tumor burden or prevent tumor progression in most patients. To enhance DC-based vaccines, we used the combination of a synthetic ligand-inducible CD40 receptor (iCD40) along with Toll-like receptor-4 (TLR-4) ligation in human monocyte-derived DCs. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo, potentially bypassing the essential role of CD4(+) T cells for activation of DCs. As a rigorous preclinical study of this approach, we evaluated key parameters of DC activation and function. Whereas neither iCD40 nor TLR-4 signaling alone led to high levels of interleukin (IL)-12p70 and IL-6, using iCD40 in combination with lipopolysaccharide (LPS) or monophosphoryl lipid A led to strongly synergistic production of both. Furthermore, this approach led to high expression of DC maturation markers, epitope-specific CTL and T helper 1 responses, as well as DC migration in vitro and in vivo. Moreover, use of iCD40-modified and LPS-stimulated DCs led to targeted expansion of autologous T cells against tumor-associated antigens, including prostate-specific membrane antigen, and elimination of preestablished tumors, supporting this technology as a potent strategy for DC-based cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Surface / immunology
  • CD40 Antigens / physiology*
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Cell Polarity
  • Dendritic Cells / immunology*
  • Glutamate Carboxypeptidase II / immunology
  • Humans
  • Interleukin-12 / biosynthesis
  • Interleukin-6 / biosynthesis
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Receptors, CCR7 / analysis
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / immunology
  • Th1 Cells / physiology
  • Toll-Like Receptor 4 / physiology*


  • Antigens, Surface
  • CCR7 protein, human
  • CD40 Antigens
  • Cancer Vaccines
  • Interleukin-6
  • Lipopolysaccharides
  • Receptors, CCR7
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Interleukin-12
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II