Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) specialized in the stimulation of naïve T lymphocytes, which are key components of antiviral and antitumor immunity. DCs are ‘sentinels’ of the immune system endowed with the mission to (1) sense invading pathogens as well as any form of tissue distress and (2) alert the effectors of the immune response. They represent a very heterogeneous population including subsets characterized by their anatomical locations and specific missions. Beyond their unique APC features, DCs exhibit a large array of effector functions that play critical roles in the induction and regulation of the cell-mediated as well as humoral immune responses. In the course of the antitumor immune response, DCs are unique in engulfing tumor cells killed by natural killer (NK) cells and cross-presenting tumor-associated antigens to cytotoxic T lymphocytes (CTLs). However, while DCs mediate antitumor immune responses by stimulating tumor-specific CTLs and NK cells, direct tumoricidal mechanisms have been recently evoked. This review addresses the other face of DCs to directly deliver apoptotic signals to stressed cells, their role in tumor cell death, and its implication in the design of DC-based cancer immunotherapies.
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Abbreviations
- Apaf-1:
-
apoptotic protease-activating factor 1
- APC:
-
antigen-presenting cell
- Bak:
-
Bcl2-antagonist/killer
- Bax:
-
Bcl2-associated X protein
- Bid:
-
BH3-interacting domain death agonist
- CRT:
-
calreticulin
- CTL:
-
cytotoxic T cell
- DC:
-
dendritic cell
- DcR:
-
decoy receptor
- DD:
-
death domain
- DED:
-
death effector domain
- Diablo:
-
direct IAP-binding family protein
- DISC:
-
death-inducing signaling complex
- FADD:
-
Fas-associated death domain
- Gas6:
-
growth arrest specific gene 6
- GZM:
-
granzyme
- IKDCs:
-
interferon-producing killer DCs
- IM:
-
Imatinib mesylate
- MFG-E8:
-
milk fat globule EGF 8
- MHC:
-
major histocompatibility complex
- NK:
-
natural killer
- pDCs:
-
plasmacytoid precursor DCs
- PFR:
-
perforin
- ROS:
-
reactive oxygen species
- Smac:
-
second mitochondria-derived activator of caspase
- TAA:
-
tumor-associated antigen
- TGF:
-
tumor growth factor
- Th:
-
T helper
- TNF:
-
tumor necrosis factor
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- Treg:
-
regulatory T cells
References
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD . Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991–998.
Lanier LL . NK cell recognition. Annu Rev Immunol 2005; 23: 225–274.
Keene JA, Forman J . Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J Exp Med 1982; 155: 768–782.
Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 2001; 411: 1058–1064.
Willimsky G, Blankenstein T . Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437: 141–146.
Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.
Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H . Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994; 264: 961–965.
Albert ML, Sauter B, Bhardwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998; 392: 86–89.
Yang L, Carbone DP . Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 2004; 92: 13–27.
Tsujitani S, Kakeji Y, Watanabe A, Kohnoe S, Maehara Y, Sugimachi K . Infiltration of dendritic cells in relation to tumor invasion and lymph node metastasis in human gastric cancer. Cancer 1990; 66: 2012–2016.
Ishigami S, Aikou T, Natsugoe S, Hokita S, Iwashige H, Tokushige M et al. Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer. Oncology 1998; 55: 65–69.
Iwamoto M, Shinohara H, Miyamoto A, Okuzawa M, Mabuchi H, Nohara T et al. Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer 2003; 104: 92–97.
Palamara F, Meindl S, Holcmann M, Luhrs P, Stingl G, Sibilia M . Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod. J Immunol 2004; 173: 3051–3061.
Zitvogel L, Casares N, Pequignot MO, Chaput N, Albert ML, Kroemer G . Immune response against dying tumor cells. Adv Immunol 2004; 84: 131–179.
Galluzzi L, Maiuri MC, Vitale I, Zischka H, Castedo M, Zitvogel L et al. Cell death modalities: classification and pathophysiological implications. Cell Death Differ 2007; 14: 1237–1243.
Lieberman J . The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol 2003; 3: 361–370.
Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA . Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 2000; 192: 755–760.
Pipkin ME, Lieberman J . Delivering the kiss of death: progress on understanding how perforin works. Curr Opin Immunol 2007; 19: 301–308.
Barry M, Bleackley RC . Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2002; 2: 401–409.
Beresford PJ, Zhang D, Oh DY, Fan Z, Greer EL, Russo ML et al. Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. J Biol Chem 2001; 276: 43285–43293.
Thomas DA, Du C, Xu M, Wang X, Ley TJ . DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis. Immunity 2000; 12: 621–632.
Pinkoski MJ, Waterhouse NJ, Green DR . Mitochondria, apoptosis and autoimmunity. Curr Dir Autoimmun 2006; 9: 55–73.
Nagata S . Apoptosis by death factor. Cell 1997; 88: 355–365.
Schaefer U, Voloshanenko O, Willen D, Walczak H . TRAIL: a multifunctional cytokine. Front Biosci 2007; 12: 3813–3824.
Kelley SK, Ashkenazi A . Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004; 4: 333–339.
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1: 489–495.
Buell JF, Gross TG, Woodle ES . Malignancy after transplantation. Transplantation 2005; 80: S254–S264.
Khong HT, Restifo NP . Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. Nat Immunol 2002; 3: 999–1005.
Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998; 95: 7556–7561.
Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E . Natural killer cells and dendritic cells: ‘l’union fait la force’. Blood 2005; 106: 2252–2258.
Shortman K, Liu YJ . Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002; 2: 151–161.
Colonna M, Trinchieri G, Liu YJ . Plasmacytoid dendritic cells in immunity. Nat Immunol 2004; 5: 1219–1226.
Le Bon A, Etchart N, Rossmann C, Ashton M, Hou S, Gewert D et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol 2003; 4: 1009–1015.
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: 107–111.
Beauvillain C, Delneste Y, Scotet M, Peres A, Gascan H, Guermonprez P et al. Neutrophils efficiently cross-prime naive T cells in vivo. Blood 2007 (PMID: 17562875).
Pozzi LA, Maciaszek JW, Rock KL . Both dendritic cells and macrophages can stimulate naive CD8T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J Immunol 2005; 175: 2071–2081.
Fuchs EJ, Matzinger P . Is cancer dangerous to the immune system? Semin Immunol 1996; 8: 271–280.
Dunn GP, Koebel CM, Schreiber RD . Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006; 6: 836–848.
Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, Steinman RM . Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 2002; 196: 1091–1097.
Steinman RM, Turley S, Mellman I, Inaba K . The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000; 191: 411–416.
Scaffidi P, Misteli T, Bianchi ME . Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191–195.
Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL . Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 2007; 13: 851–856.
Shi Y, Evans JE, Rock KL . Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003; 425: 516–521.
Rovere P, Vallinoto C, Bondanza A, Crosti MC, Rescigno M, Ricciardi-Castagnoli P et al. Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J Immunol 1998; 161: 4467–4471.
Erwig LP, Henson PM . Clearance of apoptotic cells by phagocytes. Cell Death Differ 2007 (PMID: 17571081).
Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G . MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J Clin Invest 2007; 117: 1902–1913.
Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13: 54–61.
Borg C, Terme M, Taieb J, Menard C, Flament C, Robert C et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest 2004; 114: 379–388.
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.
Moretta A . Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002; 2: 957–964.
Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 2004; 5: 1260–1265.
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.
Chaudhry UI, Katz SC, Kingham TP, Pillarisetty VG, Raab JR, Shah AB et al. In vivo overexpression of Flt3 ligand expands and activates murine spleen natural killer dendritic cells. FASEB J 2006; 20: 982–984.
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.
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.
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.
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.
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.
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.
Trinite B, Voisine C, Yagita H, Josien R . A subset of cytolytic dendritic cells in rat. J Immunol 2000; 165: 4202–4208.
Spits H, Lanier LL . Natural killer or dendritic: what's in a name? Immunity 2007; 26: 11–16.
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.
Bonmort M, Ullrich E, Mignot G, Jacobs B, Chaput N, Zitvogel L . Interferon-gamma is produced by another player of innate immune responses: the interferon-producing killer dendritic cell (IKDC). Biochimie 2007; 89: 872–877.
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.
Schuler G, Schuler-Thurner B, Steinman RM . The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003; 15: 138–147.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942–949.
Gilboa E . DC-based cancer vaccines. J Clin Invest 2007; 117: 1195–1203.
Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002; 169: 2756–2761.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004; 34: 336–344.
Ghiringhelli F, Menard C, Martin F, Zitvogel L . The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev 2006; 214: 229–238.
Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E . Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59: 3128–3133.
Steitz J, Bruck J, Lenz J, Knop J, Tuting T . 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. Cancer Res 2001; 61: 8643–8646.
Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y . CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 2006; 176: 1582–1587.
Johnson TR, Stone K, Nikrad M, Yeh T, Zong WX, Thompson CB et al. The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 2003; 22: 4953–4963.
Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J . The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 1999; 5: 2638–2645.
Wang S, El-Deiry WS . TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 2003; 22: 8628–8633.
Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999; 5: 157–163.
Di Pietro R, Zauli G . Emerging non-apoptotic functions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L. J Cell Physiol 2004; 201: 331–340.
LeBlanc HN, Ashkenazi A . Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 2003; 10: 66–75.
Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY et al. Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma. Oncogene 2001; 20: 399–403.
Seitz S, Wassmuth P, Fischer J, Nothnagel A, Jandrig B, Schlag PM et al. Mutation analysis and mRNA expression of trail-receptors in human breast cancer. Int J Cancer 2002; 102: 117–128.
Malhi H, Gores GJ . TRAIL resistance results in cancer progression: a TRAIL to perdition? Oncogene 2006; 25: 7333–7335.
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Chan, C., Housseau, F. The ‘kiss of death’ by dendritic cells to cancer cells. Cell Death Differ 15, 58–69 (2008). https://doi.org/10.1038/sj.cdd.4402235
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DOI: https://doi.org/10.1038/sj.cdd.4402235
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