Immunotherapy with dendritic cells for cancer.

Dendritic cells are professional antigen-presenting cells with a key role in both immunity induction and tolerance maintenance. Dendritic cells are highly specialized in antigen capture, processing and presentation, and express co-stimulation signals which activate T lymphocytes and NK cells. Dendritic cells generated in culture and loaded with an antigen efficiently induce antigen-specific immunity after injection. More recently, methods have been developed that target antigens to dendritic cells in vivo, bypassing the need for ex vivo cell manipulations. Numerous ongoing studies aim to evaluate the effectiveness of dendritic cell vaccines in preventing tumor relapses and extending patients' survival. Further implementation of this form of immunotherapy is expected following the identification of the mechanisms controlling dendritic cell immunogenicity, and from a better understanding of the cell dynamics whereby immune responses are orchestrated. Here, we discuss these new insights together with an overview of the dendritic cell-based clinical studies carried out to date.

[1]  E. Gilboa DC-based cancer vaccines. , 2007, The Journal of clinical investigation.

[2]  P. De Baetselier,et al.  Regulation of Dendritic Cell Numbers and Maturation by Lipopolysaccharide in Vivo , 1996 .

[3]  S. Kaveri,et al.  Human Dendritic Cells Acquire a Semimature Phenotype and Lymph Node Homing Potential through Interaction with CD4+CD25+ Regulatory T Cells1 , 2007, The Journal of Immunology.

[4]  Tae Woo Kim,et al.  Enhancing dendritic cell vaccine potency by combining a BAK/BAX siRNA‐mediated antiapoptotic strategy to prolong dendritic cell life with an intracellular strategy to target antigen to lysosomal compartments , 2007, International journal of cancer.

[5]  Edgar Schmitt,et al.  Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. , 2006, Blood.

[6]  M. Cippitelli,et al.  Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. , 1998, The Journal of clinical investigation.

[7]  T. Asano,et al.  PI3K-mediated negative feedback regulation of IL-12 production in DCs , 2002, Nature Immunology.

[8]  H. Mages,et al.  Emerging paradigms of T-cell co-stimulation. , 2004, Current opinion in immunology.

[9]  Bedford Pa,et al.  The effect of retinoids on dendritic cell function. , 1989 .

[10]  A. Aderem,et al.  Toll-like receptors in the induction of the innate immune response , 2000, Nature.

[11]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[12]  J. Fay,et al.  Expansion of Melanoma-specific Cytolytic CD8+ T Cell Precursors in Patients with Metastatic Melanoma Vaccinated with CD34+ Progenitor-derived Dendritic Cells , 2004, The Journal of experimental medicine.

[13]  D. Waber,et al.  AMITRIPTYLINE THERAPY IN PATIENTS WITH ANOREXIA NERVOSA , 1976, The Lancet.

[14]  Gerold Schuler,et al.  Dendritic Cells as Vectors for Therapy , 2001, Cell.

[15]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[16]  Sai T Reddy,et al.  In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[17]  M. Krummel,et al.  Imaging the function of regulatory T cells in vivo. , 2006, Current opinion in immunology.

[18]  W. Brugger,et al.  Dendritic Cell Immunogenicity Is Regulated by Peroxisome Proliferator-Activated Receptor γ1 , 2002, The Journal of Immunology.

[19]  A. Bringmann,et al.  TLR ligands differentially affect uptake and presentation of cellular antigens. , 2007, Blood.

[20]  R. Förster,et al.  Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. , 2002, Blood.

[21]  H. Nisenbaum,et al.  Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. , 2007, Cancer research.

[22]  Balancing life and death , 2004, Nature Immunology.

[23]  T. Luft,et al.  Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli. , 2003, Blood.

[24]  M. Görner,et al.  Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells. , 2004, Blood.

[25]  C. Figdor,et al.  Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. , 2005, Blood.

[26]  N. Shastri,et al.  In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Antonio Lanzavecchia,et al.  Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming , 2004, Nature Immunology.

[28]  R. Steinman,et al.  Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. , 1999, The Journal of clinical investigation.

[29]  E. Engleman,et al.  Dendritic cells in cancer immunotherapy. , 2000, Annual review of immunology.

[30]  S. Rosenberg,et al.  Use of standard criteria for assessment of cancer vaccines. , 2005, The Lancet. Oncology.

[31]  R. Elashoff,et al.  Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  Francesco Bertoni,et al.  Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1–polarizing program in dendritic cells , 2005, Nature Immunology.

[33]  C. Glass,et al.  Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors , 1997, Molecular and cellular biology.

[34]  Richard A. Flavell,et al.  Help for cytotoxic-T-cell responses is mediated by CD40 signalling , 1998, Nature.

[35]  Polly Matzinger,et al.  A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell , 1998, Nature.

[36]  A. Moretta Natural killer cells and dendritic cells: rendezvous in abused tissues , 2002, Nature Reviews Immunology.

[37]  W. Wilmanns,et al.  Donor Leukocyte Transfusions for Treatment of Recurrent Chronic Myelogenous Leukemia in Marrow Transplant Patients , 1990 .

[38]  J. Lehmann,et al.  A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation , 1995, Cell.

[39]  C. Figdor,et al.  Targeting antigens to dendritic cells in vivo. , 2006, Immunobiology.

[40]  L. Parijs,et al.  A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells , 2004, Nature Immunology.

[41]  V. Cerundolo,et al.  Dendritic Cell Function Can Be Modulated through Cooperative Actions of TLR Ligands and Invariant NKT Cells1 , 2007, The Journal of Immunology.

[42]  L. Hamann,et al.  Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists , 1997, Nature.

[43]  Loise M. Francisco,et al.  Immature Dendritic Cells Phagocytose Apoptotic Cells via αvβ5 and CD36, and Cross-present Antigens to Cytotoxic T Lymphocytes , 1998, The Journal of experimental medicine.

[44]  Edgar G. Engleman,et al.  Vaccination of patients with B–cell lymphoma using autologous antigen–pulsed dendritic cells , 1996, Nature Medicine.

[45]  G. Rabinovich,et al.  Immunosuppressive strategies that are mediated by tumor cells. , 2007, Annual review of immunology.

[46]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[47]  A. Bringmann,et al.  PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. , 2004, Blood.

[48]  P. Kalinski,et al.  IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. , 1997, Journal of immunology.

[49]  D. Tough,et al.  Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1 , 2006, The Journal of Immunology.

[50]  S. Akira,et al.  Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway , 2002, Nature Immunology.

[51]  I. Mellman,et al.  Defective IL‐12 production in mitogen‐activated protein (MAP) kinase kinase 3 (Mkk3)‐deficient mice , 1999, The EMBO journal.

[52]  R. Steinman,et al.  Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice , 2006 .

[53]  J. Loucká,et al.  Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming1 , 2004, The Journal of Immunology.

[54]  M. Akashi,et al.  Targeting of Antigen to Dendritic Cells with Poly(γ-Glutamic Acid) Nanoparticles Induces Antigen-Specific Humoral and Cellular Immunity1 , 2007, The Journal of Immunology.

[55]  A. Enk,et al.  Targeting of antigens to activated dendritic cells in vivo cures metastatic melanoma in mice. , 2005, Cancer research.

[56]  M. Hanna,et al.  Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial , 1999, The Lancet.

[57]  Katsuaki Sato,et al.  Extracellular Signal-Regulated Kinase, Stress-Activated Protein Kinase/c-Jun N-Terminal Kinase, and p38mapk Are Involved in IL-10-Mediated Selective Repression of TNF-α-Induced Activation and Maturation of Human Peripheral Blood Monocyte-Derived Dendritic Cells , 1999, The Journal of Immunology.

[58]  Michel C Nussenzweig,et al.  Tolerogenic dendritic cells. , 2003, Annual review of immunology.

[59]  Laurence Zitvogel,et al.  Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming , 2001, Nature Medicine.

[60]  J. Banchereau,et al.  GM-CSF and TNF-α cooperate in the generation of dendritic Langerhans cells , 1992, Nature.

[61]  E. Mittendorf,et al.  Investigating the Combination of Trastuzumab and HER2/neu Peptide Vaccines for the Treatment of Breast Cancer , 2006, Annals of Surgical Oncology.

[62]  A. Pileri,et al.  GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR TO HARVEST CIRCULATING HAEMOPOIETIC STEM CELLS FOR AUTOTRANSPLANTATION , 1989, The Lancet.

[63]  L Edler,et al.  Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[64]  P. Colville-Nash,et al.  Cyclopentenone prostaglandins—new allies in the war on inflammation , 2000, Nature Medicine.

[65]  C. Liu,et al.  Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses , 2007, The Journal of Immunology.

[66]  Lei Shen,et al.  Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity , 2004, Nature Biotechnology.

[67]  A. Ballestrero,et al.  Histone Deacetylase Inhibitors Affect Dendritic Cell Differentiation and Immunogenicity , 2007, Clinical Cancer Research.

[68]  J. Berzofsky,et al.  Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL , 1996, The Journal of experimental medicine.

[69]  Yong‐jun Liu,et al.  Development of dendritic-cell lineages. , 2007, Immunity.

[70]  H. Sandoval,et al.  Dendritic Cell Apoptosis in the Maintenance of Immune Tolerance , 2006, Science.

[71]  G. Bonadonna,et al.  Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor. , 1989, Blood.

[72]  M. Peshwa,et al.  Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  R. Germain,et al.  Dynamic Imaging of T Cell-Dendritic Cell Interactions in Lymph Nodes , 2002, Science.

[74]  L. Kanz,et al.  Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. , 2000 .

[75]  A. Anichini,et al.  Autologous dendritic cells derived from CD34+ progenitors and from monocytes are not functionally equivalent antigen-presenting cells in the induction of melan-A/Mart-1(27-35)-specific CTLs from peripheral blood lymphocytes of melanoma patients with low frequency of CTL precursors. , 1997, Cancer research.

[76]  T. Tüting,et al.  Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. , 2001, Cancer research.

[77]  C. Arteaga,et al.  Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. , 2003, Cancer research.

[78]  Peter Brossart,et al.  Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. , 2006, Cancer research.

[79]  E. Gilboa,et al.  Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. , 2007, Cancer research.

[80]  E. Bröcker,et al.  Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis. , 2000, Blood.

[81]  S. Rosenberg,et al.  Cancer immunotherapy: moving beyond current vaccines , 2004, Nature Medicine.

[82]  M. Pallardy,et al.  GILZ expression in human dendritic cells redirects their maturation and prevents antigen-specific T lymphocyte response. , 2006, Blood.

[83]  W. Cao,et al.  Innate immune functions of plasmacytoid dendritic cells. , 2007, Current opinion in immunology.

[84]  F. Sallusto,et al.  Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells , 2000, Nature Immunology.

[85]  J. Prieto,et al.  The Extra Domain A from Fibronectin Targets Antigens to TLR4-Expressing Cells and Induces Cytotoxic T Cell Responses In Vivo1 , 2007, The Journal of Immunology.

[86]  Antonio Lanzavecchia,et al.  Regulation of T Cell Immunity by Dendritic Cells , 2001, Cell.

[87]  D. Mahvi,et al.  A Phase I Study of Immunization Using Particle-Mediated Epidermal Delivery of Genes for gp100 and GM-CSF into Uninvolved Skin of Melanoma Patients , 2007, Clinical Cancer Research.

[88]  Tae Woo Kim,et al.  Vaccination with dendritic cells transfected with BAK and BAX siRNA enhances antigen-specific immune responses by prolonging dendritic cell life. , 2005, Human gene therapy.

[89]  F. Sallusto,et al.  Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha , 1994, The Journal of experimental medicine.

[90]  Steffen Jung,et al.  The Shiga toxin B‐subunit targets antigen in vivo to dendritic cells and elicits anti‐tumor immunity , 2006, European journal of immunology.

[91]  S. Sakaguchi Regulatory T cells , 2000, Cell.

[92]  P. Brossart,et al.  Cellular Immunotherapy with Dendritic Cells in Cancer: Current Status , 2004, Stem cells.

[93]  W. Lehmacher,et al.  Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial , 2004, The Lancet.

[94]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[95]  R. Steinman,et al.  Mature dendritic cells boost functionally superior CD8(+) T-cell in humans without foreign helper epitopes. , 2000, The Journal of clinical investigation.