Dendritic cell-derived exosomes for cancer therapy.

DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell-dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell-based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.

[1]  N. Kosaka,et al.  Versatile roles of extracellular vesicles in cancer. , 2016, The Journal of clinical investigation.

[2]  W. Stoorvogel,et al.  Prostasomes as a source of diagnostic biomarkers for prostate cancer. , 2016, The Journal of clinical investigation.

[3]  T. Whiteside.  Exosomes and tumor-mediated immune suppression. , 2016, The Journal of clinical investigation.

[4]  Olivier Lantz,et al.  Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC , 2015, Oncoimmunology.

[5]  Christian Pilarsky,et al.  Glypican-1 identifies cancer exosomes and detects early pancreatic cancer , 2015, Nature.

[6]  J. Castle,et al.  Mutant MHC class II epitopes drive therapeutic immune responses to cancer , 2015, Nature.

[7]  L. Zitvogel,et al.  Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients , 2015, Science Translational Medicine.

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

[9]  Sha Li,et al.  Exosome and Exosomal MicroRNA: Trafficking, Sorting, and Function , 2015, Genom. Proteom. Bioinform..

[10]  J. Barbuto,et al.  Dendritic Cell-Derived Exosomes may be a Tool for Cancer Immunotherapy by Converting Tumor Cells into Immunogenic Targets , 2015, Front. Immunol..

[11]  M. Nakayama,et al.  Antigen Presentation by MHC-Dressed Cells , 2015, Front. Immunol..

[12]  Imre Mäger,et al.  Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting , 2015, Journal of extracellular vesicles.

[13]  George A Calin,et al.  Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. , 2014, Cancer cell.

[14]  M. Bagot,et al.  IPH4102, a humanized KIR3DL2 antibody with potent activity against cutaneous T-cell lymphoma. , 2014, Cancer research.

[15]  S. Lim,et al.  Immunotherapeutic Potential of Extracellular Vesicles , 2014, Front. Immunol..

[16]  L. Zitvogel,et al.  Dendritic Cell–Derived Exosomes as Immunotherapies in the Fight against Cancer , 2014, The Journal of Immunology.

[17]  Andrea Sobo-Vujanovic,et al.  Dendritic-cell exosomes cross-present Toll-like receptor-ligands and activate bystander dendritic cells. , 2014, Cellular immunology.

[18]  P. Robbins,et al.  Regulation of immune responses by extracellular vesicles , 2014, Nature Reviews Immunology.

[19]  P. Crocker,et al.  CD169 mediates the capture of exosomes in spleen and lymph node. , 2014, Blood.

[20]  Eric Vivier,et al.  The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide , 2013, Science.

[21]  I. Mellman,et al.  Oncology meets immunology: the cancer-immunity cycle. , 2013, Immunity.

[22]  L. Zitvogel,et al.  Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. , 2013, Immunity.

[23]  C. Sautès-Fridman,et al.  Characteristics and Clinical Impacts of the Immune Environments in Colorectal and Renal Cell Carcinoma Lung Metastases: Influence of Tumor Origin , 2013, Clinical Cancer Research.

[24]  J. Blay,et al.  Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. , 2013, Cancer research.

[25]  Laurence Zitvogel,et al.  Immunogenic cell death in cancer therapy. , 2013, Annual review of immunology.

[26]  S. Gabrielsson,et al.  Dendritic Cell–Derived Exosomes Need To Activate Both T and B Cells To Induce Antitumor Immunity , 2013, The Journal of Immunology.

[27]  C. Harding,et al.  Exosomes: Looking back three decades and into the future , 2013, The Journal of cell biology.

[28]  F. Chisari,et al.  Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. , 2012, Cell host & microbe.

[29]  William J. Buchser,et al.  Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands , 2012, Oncoimmunology.

[30]  K. Hirata,et al.  Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. , 2012, Immunotherapy.

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

[32]  L. Zitvogel,et al.  Trial Watch , 2012, Oncoimmunology.

[33]  Simon C Watkins,et al.  Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. , 2012, Blood.

[34]  T. Bieber,et al.  7‐Interferon‐regulated chaperone governs human lymphocyte antigen class II expression , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  M. Caligiuri,et al.  IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. , 2011, Blood.

[36]  P. Robbins,et al.  The Roles of Tumor-Derived Exosomes in Cancer Pathogenesis , 2011, Clinical & developmental immunology.

[37]  M. Bevan,et al.  Cross-dressed dendritic cells drive memory CD8+ T-cell activation after viral infection , 2011, Nature.

[38]  R. Schreiber,et al.  Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion , 2011, Science.

[39]  L. Zitvogel,et al.  Cyclophosphamide induces differentiation of Th17 cells in cancer patients. , 2011, Cancer research.

[40]  L. Zitvogel,et al.  Updated Technology to Produce Highly Immunogenic Dendritic Cell-derived Exosomes of Clinical Grade: A Critical Role of Interferon-&ggr; , 2011, Journal of immunotherapy.

[41]  E. Alici.  IPH-2101, a fully human anti-NK-cell inhibitory receptor mAb for the potential treatment of hematological cancers. , 2010, Current opinion in molecular therapeutics.

[42]  F. L. D’Alexandri,et al.  Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. , 2010, The Journal of allergy and clinical immunology.

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

[44]  L. Zitvogel,et al.  Dendritic cell-derived exosomes for cancer immunotherapy: what's next? , 2010, Cancer research.

[45]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[46]  Laurence Zitvogel,et al.  Dendritic Cell-Derived Exosomes Promote Natural Killer Cell Activation and Proliferation: A Role for NKG2D Ligands and IL-15Rα , 2009, PloS one.

[47]  S. Gabrielsson,et al.  Antigen-loaded exosomes alone induce Th1-type memory through a B-cell-dependent mechanism. , 2009, Blood.

[48]  A. Engert,et al.  Dendritic Cells Release HLA-B-Associated Transcript-3 Positive Exosomes to Regulate Natural Killer Function , 2008, PloS one.

[49]  Xiangyang Zhou,et al.  Phase I Clinical Trial of Autologous Ascites-derived Exosomes Combined With GM-CSF for Colorectal Cancer , 2008, Molecular Therapy.

[50]  Simon C Watkins,et al.  Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition1 , 2008, The Journal of Immunology.

[51]  M. Ishii,et al.  Making friends in out‐of‐the‐way places: how cells of the immune system get together and how they conduct their business as revealed by intravital imaging , 2008, Immunological reviews.

[52]  Michael Hallek,et al.  Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. , 2007, Immunity.

[53]  A. Muntasell,et al.  T cell‐induced secretion of MHC class II–peptide complexes on B cell exosomes , 2007, The EMBO journal.

[54]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[55]  G. Raposo,et al.  T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. , 2007, Gastroenterology.

[56]  B. Chauffert,et al.  Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients , 2007, Cancer Immunology, Immunotherapy.

[57]  S. Gabrielsson,et al.  Direct exosome stimulation of peripheral humanT cells detected by ELISPOT , 2006, European journal of immunology.

[58]  R. Germain,et al.  Natural killer cell behavior in lymph nodes revealed by static and real-time imaging , 2006, The Journal of experimental medicine.

[59]  L. Zitvogel,et al.  Chemoimmunotherapy of Tumors: Cyclophosphamide Synergizes with Exosome Based Vaccines1 , 2006, The Journal of Immunology.

[60]  C. Théry,et al.  Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. , 2005, Blood cells, molecules & diseases.

[61]  C. Théry,et al.  ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. , 2005, Blood.

[62]  Olivier Lantz,et al.  Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial , 2005, Journal of Translational Medicine.

[63]  J. Le Pecq,et al.  A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer , 2005, Journal of Translational Medicine.

[64]  L. Zitvogel,et al.  Exosomes as Potent Cell-Free Peptide-Based Vaccine. I. Dendritic Cell-Derived Exosomes Transfer Functional MHC Class I/Peptide Complexes to Dendritic Cells 1 , 2004, The Journal of Immunology.

[65]  L. Zitvogel,et al.  Exosomes as Potent Cell-Free Peptide-Based Vaccine. II. Exosomes in CpG Adjuvants Efficiently Prime Naive Tc1 Lymphocytes Leading to Tumor Rejection 1 , 2004, The Journal of Immunology.

[66]  B. Chauffert,et al.  CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative , 2004, European journal of immunology.

[67]  A. Harris,et al.  Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. , 2003, Cancer research.

[68]  C. Hotta,et al.  MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. , 2003, Immunology letters.

[69]  C. Théry,et al.  Indirect activation of naïve CD4+ T cells by dendritic cell–derived exosomes , 2002, Nature Immunology.

[70]  P. Benaroch,et al.  Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. , 2002, International immunology.

[71]  P. Ricciardi-Castagnoli,et al.  Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles1 , 2001, The Journal of Immunology.

[72]  Laurence Zitvogel,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

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

[74]  D. Carbone,et al.  Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. , 1996, Cellular immunology.

[75]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[76]  M. Bergström.  From Department of Women’s and Children’s Health , 2010 .

[77]  L. Zitvogel,et al.  Exosomes for cancer immunotherapy. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.