Tumor cell loaded type-1 polarized dendritic cells induce Th1-mediated tumor immunity.
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.
Hokey
David A
DA
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Larregina
Adriana T
AT
Erdos
Geza
G
Watkins
Simon C
SC
Falo
Louis D
LD
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*
D021122:Protein Subunits; D018664:Interleukin-12; D010047:Ovalbumin; D011070:Poly I-C