Dendritic cell-based immunotherapy

Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.

[1]  W. Oyen,et al.  Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity , 2016, Cancer Immunology, Immunotherapy.

[2]  Nina Bhardwaj,et al.  CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells , 2016, PLoS pathogens.

[3]  S. Mocellin,et al.  Suppressive Influences in the Immune Response to Cancer , 2009, Journal of immunotherapy.

[4]  M. Nussenzweig,et al.  Origin and development of dendritic cells , 2010, Immunological reviews.

[5]  C. von Kalle,et al.  Lentivirus-induced ‘Smart' dendritic cells: Pharmacodynamics and GMP-compliant production for immunotherapy against TRP2-positive melanoma , 2015, Gene Therapy.

[6]  Anja ten Brinke,et al.  Comparison of media and serum supplementation for generation of monophosphoryl lipid A/interferon-γ-matured type I dendritic cells for immunotherapy. , 2014, Cytotherapy.

[7]  M. Roncarolo,et al.  Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. , 2005, Blood.

[8]  R. Steinman,et al.  Prolonged IFN-γ–producing NKT response induced with α-galactosylceramide–loaded DCs , 2002, Nature Immunology.

[9]  N. Bhardwaj,et al.  A clinical grade cocktail of cytokines and PGE2 results in uniform maturation of human monocyte-derived dendritic cells: implications for immunotherapy. , 2002, Vaccine.

[10]  P. Krause,et al.  Prostaglandin E2 is a key factor for monocyte‐derived dendritic cell maturation: enhanced T cell stimulatory capacity despite IDO , 2007, Journal of leukocyte biology.

[11]  K. Ishii,et al.  Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses , 2006, Nature.

[12]  W. Oyen,et al.  Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. , 2003, Cancer research.

[13]  R. Figlin,et al.  Survival with AGS-003, an autologous dendritic cell–based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results , 2015, Journal of Immunotherapy for Cancer.

[14]  R. Steinman,et al.  A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T‐cell immunity in vivo , 2012, European journal of immunology.

[15]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[16]  S. H. van der Burg,et al.  Addition of interferon‐α to the p53‐SLP® vaccine results in increased production of interferon‐γ in vaccinated colorectal cancer patients: A phase I/II clinical trial , 2013, International journal of cancer.

[17]  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.

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

[19]  D. Palli,et al.  Plasmacytoid dendritic cells represent a major dendritic cell subset in sentinel lymph nodes of melanoma patients and accumulate in metastatic nodes. , 2007, Clinical immunology.

[20]  S. H. van der Burg,et al.  Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients, a phase II trial , 2009, International journal of cancer.

[21]  M. Sadelain,et al.  Langerhans Cells Derived from Genetically Modified Human CD34+ Hemopoietic Progenitors Are More Potent Than Peptide-Pulsed Langerhans Cells for Inducing Antigen-Specific CD8+ Cytolytic T Lymphocyte Responses1 , 2005, The Journal of Immunology.

[22]  R. McLendon,et al.  Tetanus toxoid and CCL3 improve DC vaccines in mice and glioblastoma patients , 2015, Nature.

[23]  S. Gringhuis,et al.  Signalling through C-type lectin receptors: shaping immune responses , 2009, Nature Reviews Immunology.

[24]  Even Fossum,et al.  Vaccine molecules targeting Xcr1 on cross‐presenting DCs induce protective CD8+ T‐cell responses against influenza virus , 2015, European journal of immunology.

[25]  R. Offringa,et al.  Superior induction of anti‐tumor CTL immunity by extended peptide vaccines involves prolonged, DC‐focused antigen presentation , 2008, European journal of immunology.

[26]  Miriam Merad,et al.  The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. , 2013, Annual review of immunology.

[27]  P. Dahm,et al.  Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors. , 2001, Cancer research.

[28]  J. Wolchok,et al.  Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. , 2015, The New England journal of medicine.

[29]  S. Rosenberg,et al.  Human tumor antigens for cancer vaccine development , 1999, Immunological reviews.

[30]  T. Gajewski,et al.  Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity , 2015, Nature.

[31]  W. Oyen,et al.  Targeting of 111In-Labeled Dendritic Cell Human Vaccines Improved by Reducing Number of Cells , 2013, Clinical Cancer Research.

[32]  J. Sosman,et al.  Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma , 2016, Cell.

[33]  J. Touraine,et al.  Dendritic cells dysfunction in tumour environment. , 2008, Cancer letters.

[34]  D. Munn,et al.  IDO and tolerance to tumors. , 2004, Trends in molecular medicine.

[35]  T. Kaisho,et al.  Conservation of a chemokine system, XCR1 and its ligand, XCL1, between human and mice. , 2010, Biochemical and biophysical research communications.

[36]  S. V. Van Gool,et al.  Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines , 2016, Front. Immunol..

[37]  N. Bhardwaj,et al.  Generation of autologous peptide- and protein-pulsed dendritic cells for patient-specific immunotherapy. , 2005, Methods in molecular medicine.

[38]  Kamel Khalili,et al.  CRISPR/Cas9 and cancer targets: future possibilities and present challenges , 2016, Oncotarget.

[39]  A. Fattorossi,et al.  Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer , 2009, Cancer Immunology, Immunotherapy.

[40]  V. Kale,et al.  Umbilical cord blood-derived CD11c+ dendritic cells could serve as an alternative allogeneic source of dendritic cells for cancer immunotherapy , 2015, Stem Cell Research & Therapy.

[41]  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.

[42]  N. McGovern,et al.  Human dendritic cell subsets , 2013, Immunology.

[43]  B. Blom,et al.  Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors. , 2004, Blood.

[44]  James W. Young,et al.  Mature myeloid dendritic cell subsets have distinct roles for activation and viability of circulating human natural killer cells. , 2005, Blood.

[45]  S. Endres,et al.  Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines. , 2001, Cancer research.

[46]  R. Hruban,et al.  Immunotherapy Converts Nonimmunogenic Pancreatic Tumors into Immunogenic Foci of Immune Regulation , 2014, Cancer Immunology Research.

[47]  H. Tahara,et al.  Cytokine gene‐mediated immunotherapy: Current status and future perspectives , 2009, Cancer science.

[48]  F. Ginhoux,et al.  Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. , 2016, Immunity.

[49]  R. Steinman,et al.  Specialized role of migratory dendritic cells in peripheral tolerance induction. , 2013, The Journal of clinical investigation.

[50]  T. Eberlein,et al.  Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma1 , 2002, The Journal of Immunology.

[51]  E. Jaffee,et al.  Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  G. Lizée,et al.  Lentivirus vector-mediated expression of tumor-associated epitopes by human antigen presenting cells. , 2004, Human gene therapy.

[53]  Qizhi Tang,et al.  The Foxp3+ regulatory T cell: a jack of all trades, master of regulation , 2008, Nature Immunology.

[54]  M. Nussenzweig,et al.  Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow , 2015, The Journal of experimental medicine.

[55]  Özlem Türeci,et al.  Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy , 2016, Nature.

[56]  S. Akira,et al.  Toll-like receptors control activation of adaptive immune responses , 2001, Nature Immunology.

[57]  P. Krause,et al.  Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells. , 2009, Blood.

[58]  S. H. van der Burg,et al.  Induction of p53-Specific Immunity by a p53 Synthetic Long Peptide Vaccine in Patients Treated for Metastatic Colorectal Cancer , 2009, Clinical Cancer Research.

[59]  Anna M. Keller,et al.  Identification of a dendritic cell receptor that couples sensing of necrosis to immunity , 2009, Nature.

[60]  D. Munn,et al.  Ido expression by dendritic cells: tolerance and tryptophan catabolism , 2004, Nature Reviews Immunology.

[61]  B. Neyns,et al.  Vaccination of a Melanoma Patient with Mature Dendritic Cells Pulsed with MAGE-3 Peptides Triggers the Activity of Nonvaccine Anti-Tumor Cells1 , 2008, The Journal of Immunology.

[62]  A. Melcher,et al.  Optimization of Dendritic Cell Loading With Tumor Cell Lysates for Cancer Immunotherapy , 2008, Journal of immunotherapy.

[63]  E. Furth,et al.  Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma , 2015, Cancer Immunology Research.

[64]  B. Volkman,et al.  Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily. , 2015, Cytokine.

[65]  S. Amigorena,et al.  Cross-Presentation in Mouse and Human Dendritic Cells. , 2015, Advances in immunology.

[66]  H. Ueno,et al.  Dendritic Cells Loaded With Killed Allogeneic Melanoma Cells can Induce Objective Clinical Responses and MART-1 Specific CD8+ T-cell Immunity , 2006, Journal of immunotherapy.

[67]  R. Steinman.  Decisions about dendritic cells: past, present, and future. , 2012, Annual review of immunology.

[68]  D. Kufe,et al.  Induction of Antitumor Immunity by Vaccination of Dendritic Cells Transfected with MUC1 RNA1 , 2000, The Journal of Immunology.

[69]  M. Nussenzweig,et al.  Circulating precursors of human CD1c+ and CD141+ dendritic cells , 2015, The Journal of experimental medicine.

[70]  F. Benvenuti.  The Dendritic Cell Synapse: A Life Dedicated to T Cell Activation , 2016, Front. Immunol..

[71]  V. Pascual,et al.  Dendritic cells control B cell growth and differentiation. , 2005, Current directions in autoimmunity.

[72]  P. Schellhammer,et al.  Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  M. Manns,et al.  Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice. , 2011, The Journal of clinical investigation.

[74]  A. Douar,et al.  Major Subsets of Human Dendritic Cells Are Efficiently Transduced by Self-Complementary Adeno-Associated Virus Vectors 1 and 2 , 2007, Journal of Virology.

[75]  Michael R Stratton,et al.  High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma , 2014, Nature Medicine.

[76]  S. H. van der Burg,et al.  Phase I Immunotherapeutic Trial with Long Peptides Spanning the E6 and E7 Sequences of High-Risk Human Papillomavirus 16 in End-Stage Cervical Cancer Patients Shows Low Toxicity and Robust Immunogenicity , 2008, Clinical Cancer Research.

[77]  Gordon D. Brown,et al.  CLEC9A Is a Novel Activation C-type Lectin-like Receptor Expressed on BDCA3+ Dendritic Cells and a Subset of Monocytes , 2008, Journal of Biological Chemistry.

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

[79]  S. Senju,et al.  Pluripotent stem cells as source of dendritic cells for immune therapy , 2010, International journal of hematology.

[80]  W. Oyen,et al.  Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients , 2011, Clinical Cancer Research.

[81]  Xiaodi Wu,et al.  Transcriptional Control of Dendritic Cell Development. , 2016, Annual review of immunology.

[82]  D. Brockstedt,et al.  Promises and challenges for the development of Listeria monocytogenes-based immunotherapies , 2008, Expert review of vaccines.

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

[84]  A. Nicosia,et al.  Prime-boost regimens with adjuvanted synthetic long peptides elicit T cells and antibodies to conserved regions of HIV-1 in macaques , 2012, AIDS.

[85]  C. Figdor,et al.  Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets. , 2013, Blood.

[86]  J. Engh,et al.  Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[87]  A. Ribas,et al.  Adenovirus MART-1–engineered Autologous Dendritic Cell Vaccine for Metastatic Melanoma , 2008, Journal of immunotherapy.

[88]  S. Gallucci,et al.  The Dendritic Cell Response to Classic, Emerging, and Homeostatic Danger Signals. Implications for Autoimmunity , 2013, Front. Immunol..

[89]  F. Casagrande,et al.  Human Papillomavirus Type 16 (HPV-16) Virus-Like Particle L1-Specific CD8+ Cytotoxic T Lymphocytes (CTLs) Are Equally Effective as E7-Specific CD8+ CTLs in Killing Autologous HPV-16-Positive Tumor Cells in Cervical Cancer Patients: Implications for L1 Dendritic Cell-Based Therapeutic Vaccines , 2009, Journal of Virology.

[90]  O. Cussenot,et al.  Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA , 2004, Cancer Immunology, Immunotherapy.

[91]  R. Steinman,et al.  Prolonged IFN-gamma-producing NKT response induced with alpha-galactosylceramide-loaded DCs. , 2002, Nature immunology.

[92]  M. Headley,et al.  Visualization of immediate immune responses to pioneer metastatic cells in the lung , 2016, Nature.

[93]  S. Chen,et al.  Transduction of human PBMC-derived dendritic cells and macrophages by an HIV-1-based lentiviral vector system. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[94]  M. Nussenzweig,et al.  Defining human dendritic cell progenitors by multiparametric flow cytometry , 2015, Nature Protocols.

[95]  A. Sica,et al.  Altered macrophage differentiation and immune dysfunction in tumor development. , 2007, The Journal of clinical investigation.

[96]  B. Baban,et al.  Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. , 2004, The Journal of clinical investigation.

[97]  S. H. van der Burg,et al.  Induction of Tumor-Specific CD4+ and CD8+ T-Cell Immunity in Cervical Cancer Patients by a Human Papillomavirus Type 16 E6 and E7 Long Peptides Vaccine , 2008, Clinical Cancer Research.

[98]  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.

[99]  A. Hurley,et al.  Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers , 2015, Bone Marrow Transplantation.

[100]  P. Symonds,et al.  Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity. , 2016, Cancer research.

[101]  V. Cerundolo,et al.  Plasmacytoid dendritic cells prime IFN‐γ‐secreting melanoma‐specific CD8 lymphocytes and are found in primary melanoma lesions , 2003, European journal of immunology.

[102]  F. Powrie,et al.  Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans , 2008, The Journal of experimental medicine.

[103]  R. Schreiber,et al.  The three Es of cancer immunoediting. , 2004, Annual review of immunology.

[104]  F. Farzaneh,et al.  Semi-allogeneic dendritic cells can induce antigen-specific T-cell activation, which is not enhanced by concurrent alloreactivity , 2007, Cancer Immunology, Immunotherapy.

[105]  R. Tibshirani,et al.  In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[106]  T. Flynn,et al.  A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy. , 2009, Vaccine.

[107]  L. Mariani,et al.  Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[108]  A. Enk,et al.  Induction of Interleukin 10–Producing, Nonproliferating Cd4+ T Cells with Regulatory Properties by Repetitive Stimulation with Allogeneic Immature Human Dendritic Cells , 2000, The Journal of experimental medicine.

[109]  J. Plumas,et al.  Plasmacytoid Dendritic Cells Capture and Cross-Present Viral Antigens from Influenza-Virus Exposed Cells , 2009, PloS one.

[110]  B. Neyns,et al.  Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[111]  T. Giese,et al.  Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. , 2003, Cancer research.

[112]  R. Steinman,et al.  CD141+ dendritic cells produce prominent amounts of IFN-α after dsRNA recognition and can be targeted via DEC-205 in humanized mice. , 2013, Blood.

[113]  Nina Bhardwaj,et al.  Antigen-Specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells , 2001, The Journal of experimental medicine.

[114]  B. Baban,et al.  Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. , 2007, The Journal of clinical investigation.

[115]  F. Garrido,et al.  Role of altered expression of HLA class I molecules in cancer progression. , 2007, Advances in experimental medicine and biology.

[116]  Nina Bhardwaj,et al.  Danger signals: a time and space continuum. , 2004, Trends in molecular medicine.

[117]  C. Slingluff,et al.  Defective Human Leukocyte Antigen Class I-associated Antigen Presentation Caused by a Novel β2-Microglobulin Loss-of-function in Melanoma Cells* , 2006, Journal of Biological Chemistry.

[118]  H. Kaufman,et al.  Oncolytic viruses: focusing on the tumor microenvironment , 2015, Cancer Gene Therapy.

[119]  G. Schuler,et al.  Antigen loading of dendritic cells with whole tumor cell preparations. , 2003, Journal of immunological methods.

[120]  P. Brossart,et al.  Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells. , 2004, Blood.

[121]  N. Bhardwaj,et al.  Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity , 2005, Journal of Virology.

[122]  T. D. de Gruijl,et al.  Transcriptional Profiling of Human Dendritic Cell Populations and Models - Unique Profiles of In Vitro Dendritic Cells and Implications on Functionality and Applicability , 2013, PloS one.

[123]  Z. Berneman,et al.  Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector T cells , 2007, Journal of leukocyte biology.

[124]  Scott N. Mueller,et al.  Targeting Antigen to Clec9A Primes Follicular Th Cell Memory Responses Capable of Robust Recall , 2015, The Journal of Immunology.

[125]  George E. Katibah,et al.  Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. , 2015, Cell reports.

[126]  J. A. Lopez,et al.  Dendritic cell dysfunction in cancer: A mechanism for immunosuppression , 2005, Immunology and cell biology.

[127]  K. Drzewiecki,et al.  Spontaneous regression of metastases from melanoma: review of the literature , 2009, Melanoma research.

[128]  E. Gilboa,et al.  Cancer immunotherapy with mRNA‐transfected dendritic cells , 2004, Immunological reviews.

[129]  A. Thomson,et al.  Dendritic cells under the spell of prostaglandins. , 2003, Trends in immunology.

[130]  P. Kantoff,et al.  Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome , 2015, Clinical Cancer Research.

[131]  C. Figdor,et al.  Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[132]  C. Figdor,et al.  Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells , 2015, Clinical Cancer Research.

[133]  I. J. van Vlodrop,et al.  Th1-Polarizing Capacity of Clinical-Grade Dendritic Cells Is Triggered by Ribomunyl but Is Compromised by PGE2: The Importance of Maturation Cocktails , 2005, Journal of immunotherapy.

[134]  R. Steinman,et al.  Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A , 2011, Proceedings of the National Academy of Sciences.

[135]  R. Steinman,et al.  Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans. , 2002, Blood.

[136]  G. Schuler,et al.  Human dendritic cells transfected with either RNA or DNA encoding influenza matrix protein M1 differ in their ability to stimulate cytotoxic T lymphocytes , 2000, Gene Therapy.

[137]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[138]  P. Kantoff,et al.  Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer , 2012, Cancer Immunology, Immunotherapy.

[139]  G. Schuler,et al.  Viral vectors for dendritic cell-based immunotherapy. , 2001, Current topics in microbiology and immunology.

[140]  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.

[141]  G. Coukos,et al.  Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. , 2001, Cancer research.

[142]  N. Hacohen,et al.  Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity , 2015, Cell.

[143]  Chunxiao Wu,et al.  Antigenically Modified Human Pluripotent Stem Cells Generate Antigen-Presenting Dendritic Cells , 2015, Scientific Reports.

[144]  N. Munshi,et al.  Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. , 2011, Blood.

[145]  Y. van Kooyk.  C-type lectins on dendritic cells: key modulators for the induction of immune responses. , 2008, Biochemical Society transactions.

[146]  C. Slingluff,et al.  Vaccines, Adjuvants, and Dendritic Cell Activators--Current Status and Future Challenges. , 2015, Seminars in oncology.

[147]  O. Joffre,et al.  Cross-presentation by dendritic cells , 2012, Nature Reviews Immunology.

[148]  N. Bercovici,et al.  Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate , 2006, Cancer Immunology, Immunotherapy.

[149]  N. Sheikh,et al.  CD54 is a surrogate marker of antigen presenting cell activation , 2008, Cancer Immunology, Immunotherapy.

[150]  Jennifer G. Abelin,et al.  MHC Class I–Associated Phosphopeptides Are the Targets of Memory-like Immunity in Leukemia , 2013, Science Translational Medicine.

[151]  P. Brossart,et al.  Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA. , 2003, Blood.

[152]  T. Schumacher,et al.  Neoantigens in cancer immunotherapy , 2015, Science.

[153]  Drew A. Torigian,et al.  A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside , 2013, Clinical Cancer Research.

[154]  A. Houghton,et al.  Peptide-Loaded Langerhans Cells, Despite Increased IL15 Secretion and T-Cell Activation In Vitro, Elicit Antitumor T-Cell Responses Comparable to Peptide-Loaded Monocyte-Derived Dendritic Cells In Vivo , 2011, Clinical Cancer Research.

[155]  A. Salazar,et al.  Therapeutic In Situ Autovaccination against Solid Cancers with Intratumoral Poly-ICLC: Case Report, Hypothesis, and Clinical Trial , 2014, Cancer Immunology Research.

[156]  Even Fossum,et al.  Laser-Assisted Intradermal Delivery of Adjuvant-Free Vaccines Targeting XCR1+ Dendritic Cells Induces Potent Antitumoral Responses , 2015, The Journal of Immunology.

[157]  R. Tampé,et al.  TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Cross-Presentation , 2014, Cell.

[158]  M. Nussenzweig,et al.  Clonal analysis of human dendritic cell progenitor using a stromal cell culture. , 2015, Journal of immunological methods.

[159]  N. Bhardwaj,et al.  Primary Tumor Tissue Lysates Are Enriched in Heat Shock Proteins and Induce the Maturation of Human Dendritic Cells1 , 2001, The Journal of Immunology.

[160]  N. Bhardwaj,et al.  The apoptotic cell receptor CR3, but not αvβ5, is a regulator of human dendritic cell immunostimulatory function , 2006 .

[161]  S. Gabriel,et al.  Genomic correlates of response to CTLA-4 blockade in metastatic melanoma , 2015, Science.

[162]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[163]  P. Sabbatini,et al.  Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients , 2012, Clinical Cancer Research.

[164]  K. Shortman,et al.  Improving vaccines by targeting antigens to dendritic cells , 2009, Experimental & Molecular Medicine.

[165]  N. Bhardwaj,et al.  KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity. , 2008, The Journal of clinical investigation.

[166]  I. Davis,et al.  Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. , 2005, Blood.

[167]  Michael Poidinger,et al.  Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow , 2015, Nature Immunology.

[168]  T. Kaisho,et al.  Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. , 2016, Cancer cell.

[169]  E. Gilboa,et al.  Induction of Tumor-Specific Cytotoxic T Lymphocytes in Cancer Patients by Autologous Tumor RNA-Transfected Dendritic Cells , 2002, Annals of surgery.

[170]  J. Routy,et al.  Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. , 2010, Clinical immunology.

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

[172]  S. Amigorena,et al.  Inflammatory dendritic cells in mice and humans. , 2013, Trends in immunology.

[173]  Peter Cresswell,et al.  Pathways of antigen processing. , 2013, Annual review of immunology.

[174]  H. Mages,et al.  Induction of Potent CD8 T Cell Cytotoxicity by Specific Targeting of Antigen to Cross-Presenting Dendritic Cells In Vivo via Murine or Human XCR1 , 2015, The Journal of Immunology.

[175]  E. Shimosegawa,et al.  Clinical Trial of the Intratumoral Administration of Labeled DC Combined With Systemic Chemotherapy for Esophageal Cancer , 2012, Journal of immunotherapy.

[176]  H. Mellstedt,et al.  Dendritic cells, pulsed with lysate of allogeneic tumor cells, are capable of stimulating MHC-restricted antigen-specific antitumor T cells , 2006, Medical oncology.

[177]  C. Gomes,et al.  Antitumor dendritic cell-based vaccines: lessons from 20 years of clinical trials and future perspectives. , 2016, Translational research : the journal of laboratory and clinical medicine.

[178]  J. Medin,et al.  Lentiviral vectors in cancer immunotherapy. , 2015, Immunotherapy.

[179]  M. Hellmich,et al.  Dendritic Cell Based Tumor Vaccination in Prostate and Renal Cell Cancer: A Systematic Review and Meta-Analysis , 2011, PloS one.

[180]  Nina Bhardwaj,et al.  CD8+ T Cell Priming by Dendritic Cell Vaccines Requires Antigen Transfer to Endogenous Antigen Presenting Cells , 2010, PloS one.

[181]  A. Ballestrero,et al.  Dendritic cells transfected with tumor RNA for the induction of antitumor CTL in colorectal cancer , 2003, Cancer Gene Therapy.

[182]  N. Bhardwaj,et al.  Differentiation of Peripheral Blood Monocytes into Dendritic Cells , 2005, Current protocols in immunology.

[183]  Scott N. Mueller,et al.  Targeting Antigen to Mouse Dendritic Cells via Clec9A Induces Potent CD4 T Cell Responses Biased toward a Follicular Helper Phenotype , 2011, The Journal of Immunology.

[184]  E. Chiocca,et al.  Oncolytic Virus-Mediated Immunotherapy: A Combinatorial Approach for Cancer Treatment. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[185]  Michael Milone,et al.  Genetic engineering of T cells for adoptive immunotherapy , 2008, Immunologic research.

[186]  M. Sadelain,et al.  Lentivirus-transduced human monocyte-derived dendritic cells efficiently stimulate antigen-specific cytotoxic T lymphocytes. , 2001, Blood.

[187]  Shangtian Yang,et al.  Dendritic cells derived from pluripotent stem cells: Potential of large scale production. , 2014, World journal of stem cells.

[188]  Kui Li,et al.  Human type 2 myeloid dendritic cells produce interferon-λ and amplify interferon-α in response to hepatitis C virus infection. , 2013, Gastroenterology.

[189]  W. Agace,et al.  How vitamin A metabolizing dendritic cells are generated in the gut mucosa. , 2012, Trends in immunology.

[190]  F. Ginhoux,et al.  Comparative genomics analysis of mononuclear phagocyte subsets confirms homology between lymphoid tissue-resident and dermal XCR1+ DCs in mouse and human and distinguishes them from Langerhans cells , 2016, Journal of immunological methods.

[191]  J. Fabre.  The allogeneic response and tumor immunity , 2001, Nature Medicine.

[192]  R. Steinman,et al.  Dendritic cell‐targeted protein vaccines: a novel approach to induce T‐cell immunity , 2012, Journal of internal medicine.

[193]  E. Clark,et al.  The role of CD40 and CD154/CD40L in dendritic cells. , 2009, Seminars in immunology.

[194]  P. Robbins,et al.  Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity 1 , 2005, The Journal of Immunology.

[195]  P. Bruggen,et al.  Transduced with Lentiviruses Several MAGE Genes Using Dendritic Cells Presented by HLA-Cw 7 and Encoded by Identification of New Antigenic Peptide , 2004 .

[196]  Targeting of the non-mutated tumor antigen HER2/neu to mature dendritic cells induces an integrated immune response that protects against breast cancer in mice , 2012, Breast Cancer Research.

[197]  B. Dörken,et al.  Allogeneic partially HLA-matched dendritic cells pulsed with autologous tumor cell lysate as a vaccine in metastatic renal cell cancer , 2013, Human vaccines & immunotherapeutics.

[198]  F. Sutterwala,et al.  Sensing pathogens and danger signals by the inflammasome. , 2009, Current opinion in immunology.

[199]  C. Figdor,et al.  Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells. , 2010, Blood.

[200]  Michael Y. Gerner,et al.  Strategically localized dendritic cells promote rapid T cell responses to lymph-borne particulate antigens. , 2015, Immunity.

[201]  J. Kirkwood,et al.  alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. , 2004, Cancer research.

[202]  Thomas Felzmann,et al.  Comparative evaluation of techniques for the manufacturing of dendritic cell-based cancer vaccines , 2008, Journal of cellular and molecular medicine.

[203]  S. Kent,et al.  Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non‐human primates , 2015, European journal of immunology.

[204]  Kaibo Duan,et al.  Human Dermal CD14+ Cells Are a Transient Population of Monocyte-Derived Macrophages , 2014, Immunity.

[205]  Marij J. P. Welters,et al.  A placebo-controlled randomized HPV16 synthetic long-peptide vaccination study in women with high-grade cervical squamous intraepithelial lesions , 2012, Cancer Immunology, Immunotherapy.

[206]  E. Gilboa,et al.  Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. , 2002, The Journal of clinical investigation.

[207]  A. Alavi,et al.  A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma , 2013, Clinical Cancer Research.

[208]  L. Adorini,et al.  Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. , 2002, Human immunology.

[209]  B. Haynes,et al.  HIV-1 infection-induced apoptotic microparticles inhibit human DCs via CD44. , 2012, The Journal of clinical investigation.

[210]  E. Mittendorf.  HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ , 2013 .

[211]  Michael Poidinger,et al.  Human Tissues Contain CD141hi Cross-Presenting Dendritic Cells with Functional Homology to Mouse CD103+ Nonlymphoid Dendritic Cells , 2012, Immunity.

[212]  J. Aerts,et al.  Induction of effective therapeutic antitumor immunity by direct in vivo administration of lentiviral vectors , 2006, Gene Therapy.

[213]  K. Foon,et al.  Type 1‐polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia , 2008, Journal of leukocyte biology.

[214]  J. Connolly,et al.  Mannose Receptor Targeting of Tumor Antigen pmel17 to Human Dendritic Cells Directs Anti-Melanoma T Cell Responses via Multiple HLA Molecules , 2004, The Journal of Immunology.

[215]  F. Hodi,et al.  Enhancing the clinical activity of granulocyte‐macrophage colony‐stimulating factor‐secreting tumor cell vaccines , 2008, Immunological reviews.

[216]  A. Nowak,et al.  Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. , 2003, Cancer research.

[217]  C. Desmarais,et al.  Immune Activation and a 9-Year Ongoing Complete Remission Following CD40 Antibody Therapy and Metastasectomy in a Patient with Metastatic Melanoma , 2014, Cancer Immunology Research.

[218]  S. H. van der Burg,et al.  Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. , 2009, The New England journal of medicine.

[219]  I. Mellman,et al.  Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation , 2013, The Journal of experimental medicine.

[220]  G. Linette,et al.  IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity. , 2013, The Journal of clinical investigation.

[221]  W. Oyen,et al.  Limited Amounts of Dendritic Cells Migrate into the T-Cell Area of Lymph Nodes but Have High Immune Activating Potential in Melanoma Patients , 2009, Clinical Cancer Research.

[222]  C. Reis e Sousa.  Dendritic cells in a mature age , 2006, Nature reviews. Immunology.

[223]  L. Galluzzi,et al.  First oncolytic virus approved for melanoma immunotherapy , 2016, Oncoimmunology.

[224]  G. Heller,et al.  Mature Human Langerhans Cells Derived from CD34+ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells1 , 2004, The Journal of Immunology.

[225]  P. Carroll,et al.  Activated Lymphocyte Recruitment Into the Tumor Microenvironment Following Preoperative Sipuleucel-T for Localized Prostate Cancer , 2014, Journal of the National Cancer Institute.

[226]  E. Mardis,et al.  A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells , 2015, Science.

[227]  N. Landau,et al.  Efficient transduction of myeloid cells by an HIV-1-derived lentiviral vector that packages the Vpx accessory protein , 2012, Gene Therapy.

[228]  R. Steinman,et al.  Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody. , 2010, Blood.

[229]  Abhishek D. Garg,et al.  Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell–driven rejection of high-grade glioma , 2016, Science Translational Medicine.

[230]  Scott D. Brown,et al.  Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival , 2014, Genome research.

[231]  N. Bhardwaj,et al.  Apoptotic cells at the crossroads of tolerance and immunity. , 2005, Current topics in microbiology and immunology.

[232]  R. Khanna,et al.  Targeting CLEC9A delivers antigen to human CD141+ DC for CD4+ and CD8+T cell recognition. , 2016, JCI insight.

[233]  T. Braun,et al.  Phase Ib Trial Assessing Autologous, Tumor-pulsed Dendritic Cells as a Vaccine Administered With or Without IL-2 in Patients With Metastatic Melanoma , 2008, Journal of immunotherapy.

[234]  K. Tanabe,et al.  Cancer immunoediting from immune surveillance to immune escape , 2007, Immunology.

[235]  S. Rosenberg,et al.  Mobilization of Dendritic Cell Precursors in Patients With Cancer by Flt3 Ligand Allows the Generation of Higher Yields of Cultured Dendritic Cells , 2002, Journal of immunotherapy.

[236]  J. Nesland,et al.  Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[237]  Laurence Zitvogel,et al.  Antigen presentation and T cell stimulation by dendritic cells. , 2002, Annual review of immunology.

[238]  W. Oyen,et al.  Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients. , 2013, Cancer research.

[239]  C. Snapper,et al.  Dendritic Cells Pulsed with Intact Streptococcus pneumoniae Elicit both Protein- and Polysaccharide-specific Immunoglobulin Isotype Responses In Vivo through Distinct Mechanisms , 2002, The Journal of experimental medicine.