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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-11, Vol.65 (21), p.10059-10067
• Main Authors: HOKEY, David A, LARREGINA, Adriana T, ERDOS, Geza, WATKINS, Simon C, FALO, Louis D
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic agents; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cell Line, Tumor; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - secretion; Female; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Interleukin-12 - immunology; Interleukin-12 - secretion; Lymphocyte Activation - immunology; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Ovalbumin - immunology; Pharmacology. Drug treatments; Poly I-C - immunology; Poly I-C - pharmacology; Protein Subunits - immunology; Protein Subunits - secretion; Th1 Cells - immunology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-1692

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.