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01-07-2014 | Original Article

Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells

Authors: Britnie R. James, Erik L. Brincks, Tamara A. Kucaba, Louis Boon, Thomas S. Griffith

Published in: Cancer Immunology, Immunotherapy | Issue 7/2014

Abstract

It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8α DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8α DC (through utilization of CD8α DC-deficient Batf3 ^−/− BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3 ^−/− BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3 ^−/− BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8α DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy.

Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12(4):269–281. doi:10.1038/nri3191 PubMedCrossRef

van Mierlo GJ, Boonman ZF, Dumortier HM, den Boer AT, Fransen MF, Nouta J, van der Voort EI, Offringa R, Toes RE, Melief CJ (2004) Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication. J Immunol 173(11):6753–6759PubMedCrossRef

de Brito C, Tomkowiak M, Ghittoni R, Caux C, Leverrier Y, Marvel J (2011) CpG promotes cross-presentation of dead cell-associated antigens by pre-CD8alpha+ dendritic cells [corrected]. J Immunol 186(3):1503–1511. doi:10.4049/jimmunol.1001022 PubMedCrossRef

Shirota H, Klinman DM (2011) CpG-conjugated apoptotic tumor cells elicit potent tumor-specific immunity. Cancer Immunol Immunother 60(5):659–669. doi:10.1007/s00262-011-0973-y PubMedCrossRef

Liu C, Lou Y, Lizee G, Qin H, Liu S, Rabinovich B, Kim GJ, Wang YH, Ye Y, Sikora AG, Overwijk WW, Liu YJ, Wang G, Hwu P (2008) Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 118(3):1165–1175. doi:10.1172/JCI33583 PubMedCentralPubMed

Nierkens S, den Brok MH, Sutmuller RP, Grauer OM, Bennink E, Morgan ME, Figdor CG, Ruers TJ, Adema GJ (2008) In vivo colocalization of antigen and CpG within dendritic cells is associated with the efficacy of cancer immunotherapy. Cancer Res 68(13):5390–5396. doi:10.1158/0008-5472.CAN-07-6023 PubMedCrossRef

Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, Colonna M, Sibilia M (2012) Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 122(2):575–585. doi:10.1172/JCI61034 PubMedCentralPubMedCrossRef

den Haan JM, Lehar SM, Bevan MJ (2000) CD8(+) but not CD8(−) dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med 192(12):1685–1696CrossRef

Schulz O, Reis e Sousa C (2002) Cross-presentation of cell-associated antigens by CD8alpha+ dendritic cells is attributable to their ability to internalize dead cells. Immunology 107(2):183–189PubMedCentralPubMedCrossRef

10.

Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, Goodwin RG (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3(6):673–682PubMedCrossRef

11.

Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH (1999) Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5(2):157–163PubMedCrossRef

12.

den Hollander MW, Gietema JA, de Jong S, Walenkamp AM, Reyners AK, Oldenhuis CN, de Vries EG (2013) Translating TRAIL-receptor targeting agents to the clinic. Cancer Lett 332(2):194–201. doi:10.1016/j.canlet.2012.04.007 CrossRef

13.

Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL (2000) Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 165(5):2886–2894PubMedCrossRef

14.

Griffith TS, Broghammer EL (2001) Suppression of tumor growth following intralesional therapy with TRAIL recombinant adenovirus. Mol Ther 4(3):257–266PubMedCrossRef

15.

VanOosten RL, Griffith TS (2007) Activation of tumor-specific CD8⁺ T Cells after intratumoral Ad5-TRAIL/CpG oligodeoxynucleotide combination therapy. Cancer Res 67(24):11980–11990PubMedCrossRef

16.

Norian LA, Kresowik TP, Rosevear HM, James BR, Rosean TR, Lightfoot AJ, Kucaba TA, Schwarz C, Weydert CJ, Henry MD, Griffith TS (2012) Eradication of metastatic renal cell carcinoma after adenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL)/CpG immunotherapy. PLoS ONE 7(2):e31085. doi:10.1371/journal.pone.0031085 PubMedCentralPubMedCrossRef

17.

Nierkens S, den Brok MH, Garcia Z, Togher S, Wagenaars J, Wassink M, Boon L, Ruers TJ, Figdor CG, Schoenberger SP, Adema GJ, Janssen EM (2011) Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 71(20):6428–6437. doi:10.1158/0008-5472.CAN-11-2154 PubMedCentralPubMedCrossRef

18.

Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, Calderon B, Schraml BU, Unanue ER, Diamond MS, Schreiber RD, Murphy TL, Murphy KM (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322(5904):1097–1100. doi:10.1126/science.1164206 PubMedCentralPubMedCrossRef

19.

Hrushesky WJ, Murphy GP (1973) Investigation of a new renal tumor model. J Surg Res 15(5):327–336PubMedCrossRef

20.

James BR, Tomanek-Chalkley A, Askeland EJ, Kucaba T, Griffith TS, Norian LA (2012) Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth. J Immunol 189(3):1311–1321. doi:10.4049/jimmunol.1100587 PubMedCentralPubMedCrossRef

21.

Asselin-Paturel C, Brizard G, Pin JJ, Briere F, Trinchieri G (2003) Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody. J Immunol 171(12):6466–6477PubMedCrossRef

22.

Anderson KG, Mayer-Barber K, Sung H, Beura L, James BR, Taylor JJ, Qunaj L, Griffith TS, Vezys V, Barber DL, Masopust D (2014) Intravascular staining for discrimination of vascular and tissue leukocytes. Nat Protoc 9(1):209–222. doi:10.1038/nprot.2014.005 PubMedCrossRef

23.

Lou Y, Liu C, Kim GJ, Liu YJ, Hwu P, Wang G (2007) Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J Immunol 178(3):1534–1541PubMedCrossRef

24.

Kuwajima S, Sato T, Ishida K, Tada H, Tezuka H, Ohteki T (2006) Interleukin 15-dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation. Nat Immunol 7(7):740–746. doi:10.1038/ni1348 PubMedCrossRef

25.

Salup RR, Wiltrout RH (1986) Adjuvant immunotherapy of established murine renal cancer by interleukin 2-stimulated cytotoxic lymphocytes. Cancer Res 46(7):3358–3363PubMed

26.

Blasius AL, Giurisato E, Cella M, Schreiber RD, Shaw AS, Colonna M (2006) Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naive mouse, but a promiscuous cell surface antigen following IFN stimulation. J Immunol 177(5):3260–3265PubMedCrossRef

27.

Vinay DS, Lee SJ, Kim CH, Oh HS, Kwon BS (2012) Exposure of a distinct PDCA-1+ (CD317) B cell population to agonistic anti-4-1BB (CD137) inhibits T and B cell responses both in vitro and in vivo. PLoS ONE 7(11):e50272. doi:10.1371/journal.pone.0050272 PubMedCentralPubMedCrossRef

28.

Bao Y, Han Y, Chen Z, Xu S, Cao X (2011) IFN-alpha-producing PDCA-1+ Siglec-H- B cells mediate innate immune defense by activating NK cells. Eur J Immunol 41(3):657–668. doi:10.1002/eji.201040840 PubMedCrossRef

29.

Asselin-Paturel C, Boonstra A, Dalod M, Durand I, Yessaad N, Dezutter-Dambuyant C, Vicari A, O’Garra A, Biron C, Briere F, Trinchieri G (2001) Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol 2(12):1144–1150. doi:10.1038/ni736 PubMedCrossRef

30.

Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, Gajewski TF (2011) Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med 208(10):2005–2016. doi:10.1084/jem.20101159 PubMedCentralPubMedCrossRef

31.

Basner-Tschakarjan E, Gaffal E, O’Keeffe M, Tormo D, Limmer A, Wagner H, Hochrein H, Tuting T (2006) Adenovirus efficiently transduces plasmacytoid dendritic cells resulting in TLR9-dependent maturation and IFN-alpha production. J Gene Med 8(11):1300–1306. doi:10.1002/jgm.964 PubMedCrossRef

32.

Mattei F, Schiavoni G, Belardelli F, Tough DF (2001) IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol 167(3):1179–1187PubMedCrossRef

33.

Epardaud M, Elpek KG, Rubinstein MP, Yonekura AR, Bellemare-Pelletier A, Bronson R, Hamerman JA, Goldrath AW, Turley SJ (2008) Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res 68(8):2972–2983. doi:10.1158/0008-5472.CAN-08-0045 PubMedCrossRef

34.

Rai D, Pham NL, Harty JT, Badovinac VP (2009) Tracking the total CD8 T cell response to infection reveals substantial discordance in magnitude and kinetics between inbred and outbred hosts. J Immunol 183(12):7672–7681PubMedCentralPubMedCrossRef

35.

Seki N, Brooks AD, Carter CR, Back TC, Parsoneault EM, Smyth MJ, Wiltrout RH, Sayers TJ (2002) Tumor-specific CTL kill murine renal cancer cells using both perforin and Fas ligand-mediated lysis in vitro, but cause tumor regression in vivo in the absence of perforin. J Immunol 168(7):3484–3492PubMedCrossRef

36.

Gonzalvez F, Ashkenazi A (2010) New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 29(34):4752–4765. doi:10.1038/onc.2010.221 PubMedCrossRef

37.

Le DT, Pardoll DM, Jaffee EM (2010) Cellular vaccine approaches. Cancer J 16(4):304–310. doi:10.1097/PPO.0b013e3181eb33d7 PubMedCentralPubMedCrossRef

38.

Fanger NA, Maliszewski CR, Schooley K, Griffith TS (1999) Human dendritic cells mediate cellular apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Exp Med 190(8):1155–1164PubMedCentralPubMedCrossRef

39.

Anguille S, Lion E, Tel J, de Vries IJ, Coudere K, Fromm PD, Van Tendeloo VF, Smits EL, Berneman ZN (2012) Interleukin-15-induced CD56(+) myeloid dendritic cells combine potent tumor antigen presentation with direct tumoricidal potential. PLoS ONE 7(12):e51851. doi:10.1371/journal.pone.0051851 PubMedCentralPubMedCrossRef

40.

Tel J, Smits EL, Anguille S, Joshi RN, Figdor CG, de Vries IJ (2012) Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities. Blood 120(19):3936–3944. doi:10.1182/blood-2012-06-435941 PubMedCrossRef

41.

Griffith TS, Ferguson TA (2011) Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells. Immunity 35(4):456–466. doi:10.1016/j.immuni.2011.08.011 PubMedCentralPubMedCrossRef

42.

Krieg A, Kline J (2000) Immune effects and therapeutic applications of CpG motifs in bacterial DNA. Immunopharmacology 48(3):303–305PubMedCrossRef

43.

Gilliet M, Boonstra A, Paturel C, Antonenko S, Xu XL, Trinchieri G, O’Garra A, Liu YJ (2002) The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J Exp Med 195(7):953–958PubMedCentralPubMedCrossRef

44.

Suzuki K, Suda T, Naito T, Ide K, Chida K, Nakamura H (2005) Impaired toll-like receptor 9 expression in alveolar macrophages with no sensitivity to CpG DNA. Am J Respir Crit Care Med 171(7):707–713. doi:10.1164/rccm.200408-1078OC PubMedCrossRef

45.

Salio M, Palmowski MJ, Atzberger A, Hermans IF, Cerundolo V (2004) CpG-matured murine plasmacytoid dendritic cells are capable of in vivo priming of functional CD8 T cell responses to endogenous but not exogenous antigens. J Exp Med 199(4):567–579. doi:10.1084/jem.20031059 PubMedCentralPubMedCrossRef

46.

Yoneyama H, Matsuno K, Toda E, Nishiwaki T, Matsuo N, Nakano A, Narumi S, Lu B, Gerard C, Ishikawa S, Matsushima K (2005) Plasmacytoid DCs help lymph node DCs to induce anti-HSV CTLs. J Exp Med 202(3):425–435. doi:10.1084/jem.20041961 PubMedCentralPubMedCrossRef

47.

Lorenzi S, Mattei F, Sistigu A, Bracci L, Spadaro F, Sanchez M, Spada M, Belardelli F, Gabriele L, Schiavoni G (2011) Type I IFNs control antigen retention and survival of CD8alpha(+) dendritic cells after uptake of tumor apoptotic cells leading to cross-priming. J Immunol 186(9):5142–5150. doi:10.4049/jimmunol.1004163 PubMedCrossRef

48.

Chu KF, Dupuy DE (2014) Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer 14(3):199–208. doi:10.1038/nrc3672 PubMedCrossRef

49.

Krieg AM (2012) CpG still rocks! Update on an accidental drug. Nucleic Acid Ther 22(2):77–89. doi:10.1089/nat.2012.0340 PubMed

50.

Holoch PA, Griffith TS (2009) TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol 625(1–3):63–72. doi:10.1016/j.ejphar.2009.06.066 PubMedCentralPubMedCrossRef

51.

Micheau O, Shirley S, Dufour F (2013) Death receptors as targets in cancer. Br J Pharmacol 169(8):1723–1744. doi:10.1111/bph.12238 PubMedCrossRef

Title: Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells
Authors: Britnie R. James
Erik L. Brincks
Tamara A. Kucaba
Louis Boon
Thomas S. Griffith
Publication date: 01-07-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 7/2014
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1548-5

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