Skip to main content

Advertisement

SpringerLink
Log in

Dendritic cell based genetic immunization stimulates potent tumor protection dependent on CD8 CTL cells in the absence of autoimmunity

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Although antibodies (Abs) produced by B cells can treat cancer in certain models, T cells have been accountable for the major effector to control cancer. Immune recognition toward tyrosinase-related protein-1 (TRP-1), a melanoma associated antigen up-regulated on the surface of B16F10 melanomas, generally leads to tumor protection mediated by Abs. In this study, immunization with dendritic cells ex vivo transduced with adenovirus encoding TRP-1 stimulates immune activation and potent tumor protection mediated by CD8 T cells in the absence of autoimmune consequence. Transfer of CD8 T cells from immunized mice also leads to tumor protection. The immune activation and CD8 T cell mediated tumor protection rely on the CD4 T cell help. Thus DC based genetic immunization targeting TRP-1, an antigen usually causes Ab predominant immune recognition, is capable of stimulating potent tumor protection dependent on CD8 T cells in the absence of autoimmunity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

DC:

Dendritic cells

TRP-1 CTL:

Cytotoxic cells

TAA:

Tumor associated antigen

Ab:

Antibody

APC:

Antigen presenting cell

MAA:

Melanoma associated antigen

DC/AdTRP-1:

DC transduced with AdTRP-1

i.v.:

Intravenous

s.c.:

Subcutaneous

ADCC:

Antibody dependent cellular cytotoxicity

LCMV:

Lymphocytic choriomeningitis virus

CTLA-4:

Cytotoxic T lymphocyte antigen-4

Reference

  • Bowne WB, Srinivasan R, Wolchok JD, Hawkins WG, Blachere NE, Dyall R, Lewis JJ, Houghton AN (1999) Coupling and uncoupling of tumor immunity and autoimmunity. J Exp Med 190:1717–1722

    Article  PubMed  CAS  Google Scholar 

  • Bramson JL, Wan YH (2002) The efficacy of genetic vaccination is dependent upon the nature of the vector system and antigen. Expert Opin Biol Ther 2:75–85

    Article  PubMed  CAS  Google Scholar 

  • Buhlmann JE, Gonzalez M, Ginther B, Panoskaltsis-Mortari A, Blazar BR, Greiner DL, Rossini AA, Flavell R, Noelle RJ (1999) Cutting edge: sustained expansion of CD8+ T cells requires CD154 expression by Th cells in acute graft versus host disease. J Immunol 162:4373–4376

    PubMed  CAS  Google Scholar 

  • Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446

    Article  PubMed  CAS  Google Scholar 

  • De PR, Marigo I, Del GF, De SC, Serafini P, Cingarlini S, Tuting T, Lenz J, Basso G, Milan G, Zanovello P, Bronte V (2004) Therapeutic effectiveness of recombinant cancer vaccines is associated with a prevalent T-cell receptor alpha usage by melanoma-specific CD8+ T lymphocytes. Cancer Res 64:8068–8076

    Article  Google Scholar 

  • Guevara-Patino JA, Engelhorn ME, Turk MJ, Liu C, Duan F, Rizzuto G, Cohen AD, Merghoub T, Wolchok JD, Houghton AN (2006) Optimization of a self antigen for presentation of multiple epitopes in cancer immunity. J Clin Invest 116:1382–1390

    Article  PubMed  CAS  Google Scholar 

  • Homma S, Komita H, Sagawa Y, Ohno T, Toda G (2005) Antitumour activity mediated by CD4+ cytotoxic T lymphocytes against MHC class II-negative mouse hepatocellular carcinoma induced by dendritic cell vaccine and interleukin-12. Immunology 115:451–461

    Article  PubMed  CAS  Google Scholar 

  • Kianizad K, Marshall LA, Grinshtein N, Bernard D, Margl R, Cheng S, Beermann F, Wan Y, Bramson J (2007) Elevated frequencies of self-reactive CD8+ T cells following immunization with a xenoantigen are due to the presence of a heteroclitic CD4+ T-cell helper epitope. Cancer Res 67:6459–6467

    Article  PubMed  CAS  Google Scholar 

  • Lane C, Leitch J, Tan X, Hadjati J, Bramson JL, Wan Y (2004) Vaccination-induced autoimmune vitiligo is a consequence of secondary trauma to the skin. Cancer Res 64:1509–1514

    Article  PubMed  CAS  Google Scholar 

  • Leitch J, Fraser K, Lane C, Putzu K, Adema GJ, Zhang QJ, Jefferies WA, Bramson JL, Wan Y (2004) CTL-dependent and -independent antitumor immunity is determined by the tumor not the vaccine. J Immunol 172:5200–5205

    PubMed  CAS  Google Scholar 

  • Ludewig B, Ochsenbein AF, Odermatt B, Paulin D, Hengartner H, Zinkernagel RM (2000) Immunotherapy with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J Exp Med 191:795–804

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Urba WJ, Si L, Wang Y, Fox BA, Hu HM (2003) Anti-tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution. Eur J Immunol 33:2123–2132

    Article  PubMed  CAS  Google Scholar 

  • Malowany JI, McCormick S, Santosuosso M, Zhang X, Aoki N, Ngai P, Wang J, Leitch J, Bramson J, Wan Y, Xing Z (2006) Development of cell-based tuberculosis vaccines: genetically modified dendritic cell vaccine is a much more potent activator of CD4 and CD8 T cells than peptide- or protein-loaded counterparts. Mol Ther 13:766–775

    Article  PubMed  CAS  Google Scholar 

  • Meijer SL, Dols A, Jensen SM, Hu HM, Miller W, Walker E, Romero P, Fox BA, Urba WJ (1997) Induction of circulating tumor-reactive CD8 T cells after vaccination of melanoma patients with the gp100 209–2M peptide. J Immunother 30(2007):533–543

    Google Scholar 

  • Muhanna N, Horani A, Doron S, Safadi R (2007) Lymphocyte-hepatic stellate cell proximity suggests a direct interaction. Clin Exp Immunol 148:338–347

    Article  PubMed  CAS  Google Scholar 

  • Ramirez-Montagut T, Turk MJ, Wolchok JD, Guevara-Patino JA, Houghton AN (2003) Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity. Oncogene 22:3180–3187

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Seipp CA, Einhorn JH, Roberts B, White DE (1998) Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens 3. J Natl Cancer Inst 90:1894–1900

    Article  PubMed  CAS  Google Scholar 

  • Smith CM, Wilson NS, Waithman J, Villadangos JA, Carbone FR, Heath WR, Belz GT (2004) Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat Immunol 5:1143–1148

    Article  PubMed  CAS  Google Scholar 

  • Steitz J, Bruck J, Lenz J, Buchs S, Tuting T (2005) Peripheral CD8+ T cell tolerance against melanocytic self-antigens in the skin is regulated in two steps by CD4+ T cells and local inflammation: implications for the pathophysiology of vitiligo. J Invest Dermatol 124:144–150

    Article  PubMed  CAS  Google Scholar 

  • Steitz J, Tormo D, Schweichel D, Tuting T (2006) Comparison of recombinant adenovirus and synthetic peptide for DC-based melanoma vaccination. Cancer Gene Ther 13:318–325

    Article  PubMed  CAS  Google Scholar 

  • Trcka J, Moroi Y, Clynes RA, Goldberg SM, Bergtold A, Perales MA, Ma M, Ferrone CR, Carroll MC, Ravetch JV, Houghton AN (2002) Redundant and alternative roles for activating Fc receptors and complement in an antibody-dependent model of autoimmune vitiligo. Immunity 16:861–868

    Article  PubMed  CAS  Google Scholar 

  • Uchi H, Stan R, Turk MJ, Engelhorn ME, Rizzuto GA, Goldberg SM, Wolchok JD, Houghton AN (2006) Unraveling the complex relationship between cancer immunity and autoimmunity: lessons from melanoma and vitiligo. Adv Immunol 90:215–241

    Article  PubMed  CAS  Google Scholar 

  • Wan Y, Bramson J, Pilon A, Zhu Q, Gauldie J (2000) Genetically modified dendritic cells prime autoreactive T cells through a pathway independent of CD40L and interleukin 12: implications for cancer vaccines. Cancer Res 60:3247–3253

    PubMed  CAS  Google Scholar 

  • Wan Y, Lu L, Bramson JL, Baral S, Zhu Q, Pilon A, Dayball K (2001) Dendritic cell-derived IL-12 is not required for the generation of cytotoxic, IFN-gamma-secreting, CD8 (+) CTL in vivo. J Immunol 167:5027–5033

    PubMed  CAS  Google Scholar 

  • Weber LW, Bowne WB, Wolchok JD, Srinivasan R, Qin J, Moroi Y, Clynes R, Song P, Lewis JJ, Houghton AN (1998) Tumor immunity and autoimmunity induced by immunization with homologous DNA. J Clin Invest 102:1258–1264

    Article  PubMed  CAS  Google Scholar 

  • Wiethe C, Schiemann M, Busch D, Haeberle L, Kopf M, Schuler G, Lutz MB (2007) Interdependency of MHC class II/self-peptide and CD1d/self-glycolipid presentation by TNF-matured dendritic cells for protection from autoimmunity. J Immunol 178:4908–4916

    PubMed  CAS  Google Scholar 

  • Yang TC, Millar J, Groves T, Grinshtein N, Parsons R, Takenaka S, Wan Y, Bramson JL (2006) The CD8+ T cell population elicited by recombinant adenovirus displays a novel partially exhausted phenotype associated with prolonged antigen presentation that nonetheless provides long-term immunity. J Immunol 176:200–210

    PubMed  CAS  Google Scholar 

  • Yang TC, Millar J, Groves T, Zhou W, Grinshtein N, Parsons R, Evelegh C, Xing Z, Wan Y, Bramson J (2007) On the role of CD4+ T cells in the CD8+ T-cell response elicited by recombinant adenovirus vaccines. Mol Ther 15:997–1006

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Wang Q, Li WF, Wang HY, Zhang HJ (2004) Enhanced antitumor immunity by murine cytokine activated T lymphocytes after cocultured with bone marrow derived dendritic cells pulsed with whole tumor lysates. Leuk Res 28:1085–1088

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Oncology, First People’s Hospital, Shanghai Jiaotong University, 85 Wujin Road, Shanghai, 200080, China

    Sheng Zhang & Weiyi Huang

Authors
  1. Sheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weiyi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sheng Zhang.

Additional information

Grant support to S.Zhang from First people’s hospital, Shanghai Jiaotong University.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, S., Huang, W. Dendritic cell based genetic immunization stimulates potent tumor protection dependent on CD8 CTL cells in the absence of autoimmunity. J Cancer Res Clin Oncol 134, 987–994 (2008). https://doi.org/10.1007/s00432-008-0368-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-008-0368-4

Keywords

Search

Navigation