Download PDF
Horm Metab Res 2008; 40(2): 75-81
DOI: 10.1055/s-2007-1022554
Review

© Georg Thieme Verlag KG Stuttgart · New York

Killer Dendritic Cells and their Potential Role in Immunotherapy

E. Ullrich 1 , 2 , N. Chaput 1 , 2 , 3 , L. Zitvogel 1 , 2 , 3 , 4
  • 1Institut Gustave Roussy, Villejuif, France
  • 2INSERM, U805, Villejuif, France
  • 3Center of Clinical Investigation CBT507, Biotherapy, Villejuif, France
  • 4Université Paris-Sud, Villejuif, France
Further Information

Publication History

received 04.10.2007

accepted 25.10.2007

Publication Date:
19 February 2008 (online)

Also available at
    Permissions and Reprints

Abstract

Tumor immunosurveillance is mediated by innate and adaptive components of cellular immunity. A complex network of cellular interactions is needed to elicit protective antitumoral CD4+and CD8+T cell responses. Thereby dendritic cells (DCs) play a central role as professional antigen presenting cells (APCs) that take up antigens, process, and present them to prime naïve T cells. Recognition and lysis of tumor cells has been attributed to innate effectors such as natural killer (NK), NKT and γδT cells. Recently, novel subsets of cytotoxic DCs, called “killer DCs” (KDCs), have been reported in rodents and humans. Killer dendritic cells could directly link innate and adaptive immunity. This review aims at comparing the different KDC populations, their phenotypes, killer function, and their potential application for anticancer immunotherapy.

Key words

tumor immunity - immunotherapy - IKDC - NK - dendritic cells - killer dendritic cells - NKDC - T cells - regulatory T cells - interferon

References

  • 1 Ehrlich P. Über den jetztigen Stand der Karzinomforschung.  Ned Tijdschr Geneeskd. 1909;  5 ((1)) 273-290
    PubMedGoogle Scholar
  • 2 Burnet M. Cancer; a biological approach. I. The processes of control.  Br Med J. 1957;  1 ((5022)) 779-786
    PubMedGoogle Scholar
  • 3 Burnet FM. The concept of immunological surveillance.  Prog Exp Tumor Res. 1970;  13 1-27
    PubMedGoogle Scholar
  • 4 Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity.  Adv Immunol. 2006;  90 1-50
    CrossrefPubMedGoogle Scholar
  • 5 Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution.  J Exp Med. 1973;  137 1142-1162
    CrossrefPubMedGoogle Scholar
  • 6 Steinman RM, Banchereau J. Taking dendritic cells into medicine.  Nature. 2007;  449 ((7161)) 419-426
    CrossrefPubMedGoogle Scholar
  • 7 Banchereau J, Steinman RM. Dendritic cells and the control of immunity.  Nature. 1998;  392 ((6673)) 245-252
    CrossrefPubMedGoogle Scholar
  • 8 Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E. et al . Distinct dendritic cell subsets differentially regulate the class of immune response in vivo.  Proc Natl Acad Sci USA. 1999;  96 1036-1041
    CrossrefPubMedGoogle Scholar
  • 9 Maldonado-Lopez R, Smedt T De, Michel P, Godfroid J, Pajak B, Heirman C. et al . CD8alpha+ and CD8alpha- subclasses of dendritic cells direct the development of distinct T helper cells in vivo.  J Exp Med. 1999;  189 587-592
    CrossrefPubMedGoogle Scholar
  • 10 Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells.  Nat Immunol. 2005;  6 769-776
    CrossrefPubMedGoogle Scholar
  • 11 Seder RA, Paul WE, Davis MM, Fazekas de St GB. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.  J Exp Med. 1992;  176 1091-1098
    CrossrefPubMedGoogle Scholar
  • 12 LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV. et al . Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.  Nat Immunol. 2007;  8 630-638
    CrossrefPubMedGoogle Scholar
  • 13 Luo X, Tarbell KV, Yang H, Pothoven K, Bailey SL, Ding R. et al . Dendritic cells with TGF-beta1 differentiate naive CD4+.  Proc Natl Acad Sci USA. 2007;  104 2821-2826
    CrossrefPubMedGoogle Scholar
  • 14 Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.  J Exp Med. 2000;  192 1213-1222
    CrossrefPubMedGoogle Scholar
  • 15 Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M. et al . Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.  J Exp Med. 2001;  194 769-779
    CrossrefPubMedGoogle Scholar
  • 16 Probst HC, MacCoy K, Okazaki T, Honjo T, van den BM. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4.  Nat Immunol. 2005;  6 280-286
    CrossrefPubMedGoogle Scholar
  • 17 Jego G, Pascual V, Palucka AK, Banchereau J. Dendritic cells control B cell growth and differentiation.  Curr Dir Autoimmun. 2005;  8 124-139
    PubMedGoogle Scholar
  • 18 Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M. et al . Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo.  Nat Med. 1999;  5 405-411
    PubMedGoogle Scholar
  • 19 Kadowaki N, Antonenko S, Ho S, Rissoan MC, Soumelis V, Porcelli SA. et al . Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells.  J Exp Med. 2001;  193 1221-1226
    CrossrefPubMedGoogle Scholar
  • 20 Schuler G, Schuler-Thurner B, Steinman RM. The use of dendritic cells in cancer immunotherapy.  Curr Opin Immunol. 2003;  15 138-147
    CrossrefPubMedGoogle Scholar
  • 21 Schott M. Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers.  Endocr Relat Cancer. 2006;  13 779-795
    CrossrefPubMedGoogle Scholar
  • 22 Ullrich E, Menard C, Flament C, Terme M, Mignot G, Bonmort M. et al . Dendritic cells and innate defense against tumor cells.  Cytokine Growth Factor Rev. 2007;  doi: 10.1016/j. cytogfr. 2007. 10. 009
    PubMedGoogle Scholar
  • 23 Ghiringhelli F, Apetoh L, Housseau F, Kroemer G, Zitvogel L. Links between innate and cognate tumor immunity.  Curr Opin Immunol. 2007;  19 224-231
    CrossrefPubMedGoogle Scholar
  • 24 Ullrich E, Bonmort M, Mignot G, Kroemer G, Zitvogel L. Tumor stress, cell death and the ensuing immune response.  Cell Death Differ. 2008;  15 21-28
    CrossrefPubMedGoogle Scholar
  • 25 Wesa A, Storkus WJ. Killer dendritic cells: Mechanisms of action and therapeutic implications for cancer.  Cell Death Differ. 2008;  15 51-57
    CrossrefPubMedGoogle Scholar
  • 26 Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development.  Nat Rev Immunol. 2007;  7 19-30
    CrossrefPubMedGoogle Scholar
  • 27 Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.  Science. 2001;  294 ((5546)) 1540-1543
    CrossrefPubMedGoogle Scholar
  • 28 Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O. et al . Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.  J Exp Med. 2005;  202 135-143
    CrossrefPubMedGoogle Scholar
  • 29 Shortman K, Liu YJ. Mouse and human dendritic cell subtypes.  Nat Rev Immunol. 2002;  2 151-161
    CrossrefPubMedGoogle Scholar
  • 30 Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S. et al . Differential antigen processing by dendritic cell subsets in vivo.  Science. 2007;  315 ((5808)) 107-111
    CrossrefPubMedGoogle Scholar
  • 31 Soares H, Waechter H, Glaichenhaus N, Mougneau E, Yagita H, Mizenina O. et al . A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo.  J Exp Med. 2007;  204 1095-1106
    CrossrefPubMedGoogle Scholar
  • 32 Kissenpfennig A, Malissen B. Langerhans cells-revisiting the paradigm using genetically engineered mice.  Trends Immunol. 2006;  27 132-139
    CrossrefPubMedGoogle Scholar
  • 33 Suss G, Shortman K. A subclass of dendritic cells kills CD4T cells via Fas/Fas-ligand-induced apoptosis.  J Exp Med. 1996;  183 1789-1796
    CrossrefPubMedGoogle Scholar
  • 34 Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DH, Thomson AW. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation.  J Immunol. 1997;  158 5676-5684
    PubMedGoogle Scholar
  • 35 Shibaki A, Katz SI. Activation through CD40 ligation induces functional Fas ligand expression by Langerhans cells.  Eur J Immunol. 2001;  31 3006-3015
    CrossrefPubMedGoogle Scholar
  • 36 Josien R, Heslan M, Soulillou JP, Cuturi MC. Rat spleen dendritic cells express natural killer cell receptor protein 1 (NKR-P1) and have cytotoxic activity to select targets via a Ca2+-dependent mechanism.  J Exp Med. 1997;  186 467-472
    CrossrefPubMedGoogle Scholar
  • 37 Trinite B, Voisine C, Yagita H, Josien R. A subset of cytolytic dendritic cells in rat.  J Immunol. 2000;  165 4202-4208
    PubMedGoogle Scholar
  • 38 Trinite B, Chauvin C, Peche H, Voisine C, Heslan M, Josien R. Immature CD4- CD103+ rat dendritic cells induce rapid caspase-independent apoptosis-like cell death in various tumor and nontumor cells and phagocytose their victims.  J Immunol. 2005;  175 2408-2417
    PubMedGoogle Scholar
  • 39 Alli R, Savithri B, Das S, Varalakshmi C, Rangaraj N, Khar A. Involvement of NKR-P2/NKG2D in DC-mediated killing of tumor targets: indicative of a common, innate, target-recognition paradigm?.  Eur J Immunol. 2004;  34 1119-1126
    CrossrefPubMedGoogle Scholar
  • 40 Srivastava RM, Varalakshmi C, Khar A. Cross-linking a mAb to NKR-P2/NKG2D on dendritic cells induces their activation and maturation leading to enhanced anti-tumor immune response.  Int Immunol. 2007;  19 591-607
    CrossrefPubMedGoogle Scholar
  • 41 Homann D, Jahreis A, Wolfe T, Hughes A, Coon B, Stipdonk MJ van. et al . CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells.  Immunity. 2002;  16 403-415
    CrossrefPubMedGoogle Scholar
  • 42 Pillarisetty VG, Katz SC, Bleier JI, Shah AB, Dematteo RP. Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-gamma via autocrine IL-12.  J Immunol. 2005;  174 2612-2618
    PubMedGoogle Scholar
  • 43 Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M. et al . A novel dendritic cell subset involved in tumor immunosurveillance.  Nat Med. 2006;  12 214-219
    PubMedGoogle Scholar
  • 44 Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M. et al . Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity.  Nat Med. 2006;  12 207-213
    PubMedGoogle Scholar
  • 45 Chaudhry UI, Kingham TP, Plitas G, Katz SC, Raab JR, Dematteo RP. Combined stimulation with interleukin-18 and CpG induces murine natural killer dendritic cells to produce IFN-{gamma} and inhibit tumor growth.  Cancer Res. 2006;  66 10497-10504
    CrossrefPubMedGoogle Scholar
  • 46 Shortman K, Villadangos JA. Is it a DC, is it an NK? No, it's an IKDC.  Nat Med. 2006;  12 167-168
    PubMedGoogle Scholar
  • 47 Ullrich E, Bonmort M, Mignot G, Chaput N, Taieb J, Menard C. et al . Therapy-induced tumor immunosurveillance involves IFN-producing killer dendritic cells.  Cancer Res. 2007;  67 851-853
    CrossrefPubMedGoogle Scholar
  • 48 Vremec D, O’Keeffe M, Hochrein H, Fuchsberger M, Caminschi I, Lahoud M. et al . Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells and interferon-producing killer dendritic cells.  Blood. 2007;  109 1165-1173
    PubMedGoogle Scholar
  • 49 Bonmort M, Ullrich E, Mignot G, Chaput N, Zitvogel L. Interferon-gamma is produced by another player of immune responses: the interferon-producing killer dendritic cell (IKDC).  Biochimie. 2007;  89 872-877
    CrossrefPubMedGoogle Scholar
  • 50 Huang J, Tatsumi T, Pizzoferrato E, Vujanovic N, Storkus WJ. Nitric oxide sensitizes tumor cells to dendritic cell-mediated apoptosis, uptake, and cross-presentation.  Cancer Res. 2005;  65 8461-8470
    CrossrefPubMedGoogle Scholar
  • 51 Tatsumi T, Huang J, Gooding WE, Gambotto A, Robbins PD, Vujanovic NL. et al . Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.  Cancer Res. 2003;  63 6378-6386
    PubMedGoogle Scholar
  • 52 Srivastava RM, Varalakshmi C, Khar A. Cross-linking a mAb to NKR-P2/NKG2D on dendritic cells induces their activation and maturation leading to enhanced anti-tumor immune response.  Int Immunol. 2007;  19 591-607
    CrossrefPubMedGoogle Scholar
  • 53 Liu YJ. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity.  Cell. 2001;  106 259-262
    CrossrefPubMedGoogle Scholar
  • 54 MacDonald KP, Munster DJ, Clark GJ, Dzionek A, Schmitz J, Hart DN. Characterization of human blood dendritic cell subsets.  Blood. 2002;  100 4512-4520
    CrossrefPubMedGoogle Scholar
  • 55 Randolph GJ, Sanchez-Schmitz G, Liebman RM, Schakel K. The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting.  J Exp Med. 2002;  196 517-527
    CrossrefPubMedGoogle Scholar
  • 56 Schakel K, Mayer E, Federle C, Schmitz M, Riethmuller G, Rieber EP. A novel dendritic cell population in human blood: one-step immunomagnetic isolation by a specific mAb (M-DC8) and in vitro priming of cytotoxic T lymphocytes.  Eur J Immunol. 1998;  28 4084-4093
    CrossrefPubMedGoogle Scholar
  • 57 Schakel K, Kannagi R, Kniep B, Goto Y, Mitsuoka C, Zwirner J. et al . 6-Sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells.  Immunity. 2002;  17 289-301
    CrossrefPubMedGoogle Scholar
  • 58 Fanger NA, Maliszewski CR, Schooley K, Griffith TS. Human dendritic cells mediate cellular apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).  J Exp Med. 1999;  190 1155-1164
    CrossrefPubMedGoogle Scholar
  • 59 Janjic BM, Lu G, Pimenov A, Whiteside TL, Storkus WJ, Vujanovic NL. Innate direct anticancer effector function of human immature dendritic cells. I. Involvement of an apoptosis-inducing pathway.  J Immunol. 2002;  168 1823-1830
    PubMedGoogle Scholar
  • 60 Lu G, Janjic BM, Janjic J, Whiteside TL, Storkus WJ, Vujanovic NL. Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis-inducing ligand.  J Immunol. 2002;  168 1831-1839
    PubMedGoogle Scholar
  • 61 Schmitz M, Zhao S, Deuse Y, Schakel K, Wehner R, Wohner H. et al . Tumoricidal potential of native blood dendritic cells: direct tumor cell killing and activation of NK cell-mediated cytotoxicity.  J Immunol. 2005;  174 4127-4134
    PubMedGoogle Scholar
  • 62 Schmitz M, Zhao S, Schakel K, Bornhauser M, Ockert D, Rieber EP. Native human blood dendritic cells as potent effectors in antibody-dependent cellular cytotoxicity.  Blood. 2002;  100 1502-1504
    PubMedGoogle Scholar
  • 63 Stary G, Bangert C, Tauber M, Strohal R, Kopp T, Stingl G. Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells.  J Exp Med. 2007;  204 1441-1451
    CrossrefPubMedGoogle Scholar
  • 64 Vanderheyde N, Aksoy E, Amraoui Z, Vandenabeele P, Goldman M, Willems F. Tumoricidal activity of monocyte-derived dendritic cells: evidence for a caspase-8-dependent, Fas-associated death domain-independent mechanism.  J Immunol. 2001;  167 3565-3569
    PubMedGoogle Scholar
  • 65 Vanderheyde N, Vandenabeele P, Goldman M, Willems F. Distinct mechanisms are involved in tumoristatic and tumoricidal activities of monocyte-derived dendritic cells.  Immunol Lett. 2004;  91 99-101
    CrossrefPubMedGoogle Scholar
  • 66 Vidalain PO, Azocar O, Yagita H, Rabourdin-Combe C, Servet-Delprat C. Cytotoxic activity of human dendritic cells is differentially regulated by double-stranded RNA and CD40 ligand.  J Immunol. 2001;  167 3765-3772
    PubMedGoogle Scholar
  • 67 Yang R, Xu D, Zhang A, Gruber A. Immature dendritic cells kill ovarian carcinoma cells by a FAS/FASL pathway, enabling them to sensitize tumor-specific CTLs.  Int J Cancer. 2001;  94 407-413
    CrossrefPubMedGoogle Scholar
  • 68 Chapoval AI, Tamada K, Chen L. In vitro growth inhibition of a broad spectrum of tumor cell lines by activated human dendritic cells.  Blood. 2000;  95 2346-2351
    PubMedGoogle Scholar
  • 69 Shi J, Ikeda K, Fujii N, Kondo E, Shinagawa K, Ishimaru F. et al . Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells.  Cancer Sci. 2005;  96 127-133
    CrossrefPubMedGoogle Scholar
  • 70 Liu S, Yu Y, Zhang M, Wang W, Cao X. The involvement of TNF-alpha-related apoptosis-inducing ligand in the enhanced cytotoxicity of IFN-beta-stimulated human dendritic cells to tumor cells.  J Immunol. 2001;  166 5407-5415
    PubMedGoogle Scholar
  • 71 Korthals M, Safaian N, Kronenwett R, Maihofer D, Schott M, Papewalis C. et al . Monocyte derived dendritic cells generated by IFN-alpha acquire mature dendritic and natural killer cell properties as shown by gene expression analysis.  J Transl Med. 2007;  5 46
    CrossrefPubMedGoogle Scholar
  • 72 Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer.  Cancer. 2000;  89 2646-2654
    CrossrefPubMedGoogle Scholar

Correspondence

L. ZitvogelMD, PhD 

U805 INSERM and CBT507

Center of Clinical Investigations

Institut Gustave Roussy

39 rue Camille Desmoulins

94805 Villejuif

France

Phone: +33/1/42 11 50 41

Fax: +33/1/42 11 60 94

Email: zitvogel@igr.fr

      >