Tumor cell loaded type-1 polarized dendritic cells induce Th1-mediated tumor immunity

Cancer Res. 2005 Nov 1;65(21):10059-67. doi: 10.1158/0008-5472.CAN-05-1692.

Abstract

Dendritic cells are professional antigen-presenting cells capable of inducing and regulating innate and antigen-specific immune responses. Therapeutic cancer vaccines using ex vivo engineered or in vivo targeted dendritic cells are being evaluated in clinical trials. T-helper type-1 (Th1)-skewed immune responses are characterized by the preferential induction of antigen-specific IFN-gamma-secreting CD4+ T cells and correlate with effector mechanisms important for tumor and viral immunity. Methods to "polarize" human monocyte-derived dendritic cells for the preferential induction of Th1-skewed immune responses have been developed, and polarized dendritic cells (DC1s) are being evaluated in preclinical and clinical studies. Here, we show that stimulation of bone marrow-derived murine dendritic cell populations with poly(I:C) and CpGs results in phenotypic maturation of dendritic cells and synergistic induction of durable, high-level IL-12p70 secretion characteristic of human type-1 polarized dendritic cells. Functionally, these dendritic cells induce antigen-specific Th1-type CD4+ T-cell activation in vitro and in vivo. Dendritic cell maturation and polarization are not inhibited by the presence of live B16 melanoma tumor cells, and tumor-loaded DC1s induce delayed-type hypersensitivity responses in vivo. DC1s loaded with B16 melanoma cells and injected into tumor-bearing mice induce Th1-skewed tumor-specific CD4+ T cells and a significant reduction in tumor growth. Tumor infiltrates in DC1-immunized animals are characterized by the presence of CD4+ T cells and activated macrophages. These results show a murine model of DC1 function and suggest an important role for CD4+ T cells and macrophages in DC1-induced antitumor immune responses. They have implications for the future development of DC1-based immunotherapies and strategies for clinical immune monitoring of their effectiveness.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Lymphocyte Activation / immunology
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Ovalbumin / immunology
  • Poly I-C / immunology
  • Poly I-C / pharmacology
  • Protein Subunits / immunology
  • Protein Subunits / metabolism
  • Th1 Cells / immunology*

Substances

  • Protein Subunits
  • Interleukin-12
  • Ovalbumin
  • Poly I-C