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CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged

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Abstract

Aim

There is accumulative evidence indicating that targeting antigen presenting cells (APCs) with different types of adjuvants could result in the induction of antitumor immune responses. It has been hypothesized that APCs function may be altered in the elderly contributing to a decline in the immune function. We evaluated whether targeting APCs following injection with Poly I:C, LPS, flagellin, imiquimod and CpG-ODN would induce an antitumor response in the old.

Materials and methods

The immune and antitumor responses induce Poly I:C, LPS, flagellin, imiquimod and CpG-ODN were compared in young (2 month old) and old (18 months) mice.

Results

Our results indicated that only intratumoral (i.t.) injections of CpG-ODN completely rejected the tumor in both young and old mice. Injections of Poly I:C also induced the rejection of tumors in the young but not in the old. Furthermore, i.t. injections of CpG-ODN promoted the development of protective memory responses in the young and the old. Analysis of the immune responses in the old indicated that CpG-ODN but not Poly-I:C induces: a pro-inflammatory Th1 type response; accumulation and activation of CD4+, CD8+ T and, NK cell responses; activation of APCs; and reduction in the number of Tregs. The activation of these immune-parameters positively correlates with the induction of an antitumor response.

Conclusions

These studies indicate that there are differences in the level of stimulation with TLR-ligands between young and old APCs and that the aged immune responses can be rescued and exploited for the induction of tumor immunity by targeting APCs with specific TLR-ligands. These results have important clinical implications for developing immunization strategies containing TLR-ligands that will be effective in both the young and old.

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References

  1. Alignani DO, et al (2005) Orally administered OVA/CpG-ODN induces specific mucosal and systemic immune response in young and aged mice. J Leukoc Biol 77:898–905

    Article  PubMed  CAS  Google Scholar 

  2. Baines J, Celis E (2003) Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 9(7):2693–2700

    PubMed  CAS  Google Scholar 

  3. Bhattacharyya S, et al (2004) Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the P13K/Akt pathway and of IkappaB kinase activity. Blood 104(4):1100–1109

    Article  PubMed  CAS  Google Scholar 

  4. Caslte SC, et al (1999) Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol 34(2):243–252

    Article  Google Scholar 

  5. Castle SC, et al (1999) Antigen presenting cell function is enhanced in healthy elderly. Mech Ageing Dev 107:137–145

    Article  PubMed  CAS  Google Scholar 

  6. Cuadros C, et al (2004) Flagellin fusion proteins as adjuvants or vaccines induce specific immune responses in aged animals. J Immunol 72:2810–2816

    CAS  Google Scholar 

  7. Deng Y, et al (2004) Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol 172(6):3437–3446

    PubMed  CAS  Google Scholar 

  8. Edwards AD, et al (2003) Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol 33(4):827–833

    Article  PubMed  CAS  Google Scholar 

  9. Esche C, Shurin MR, Lotze MT (1999) The use of dendritic cells for cancer vaccination. Curr Opin Mol Ther 1(1):72–81

    PubMed  CAS  Google Scholar 

  10. Forsey RJ, et al (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124(4):487–493

    Article  PubMed  CAS  Google Scholar 

  11. Foster BA, et al (1997) Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res 57(16):3325–3330

    PubMed  CAS  Google Scholar 

  12. Grewe M (2001) Chronological ageing and photoageing of dendritic cells. Clin Exp Dermatol 26:608–612

    Article  PubMed  CAS  Google Scholar 

  13. Hawlisch H, Kohl J (2006) Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol Immunol 43:13–21

    Article  PubMed  CAS  Google Scholar 

  14. Janeway CA Jr, et al (1989) Cross-linking and conformational change in T-cell receptors: role in activation and in repertoire selection. Cold Spring Harb Symp Quant Ciol 54(Pt 2):657–666

    CAS  Google Scholar 

  15. Kadowaki N, et al (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869

    Article  PubMed  CAS  Google Scholar 

  16. Kaisho T, Akira S (2003) Regulation of dendritic cell function through Toll-like receptors. Curr Mol Med 3:373–385

    Article  PubMed  CAS  Google Scholar 

  17. Lin W, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183

    Article  PubMed  CAS  Google Scholar 

  18. Lung TL, et al (2000) Unimpaired dendrititc cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine 18:1606–1612

    Article  PubMed  CAS  Google Scholar 

  19. Lustgarten J, Dominguez AL, Thoman M (2004) Aged mice develop protective antitumor immune responses with appropriate costimulation. J Immunol 173:4510–4515

    PubMed  CAS  Google Scholar 

  20. Maletto B, et al (2002) CpG-DNA stimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice. J Leukoc Biol 72(3):447–454

    PubMed  CAS  Google Scholar 

  21. Martin M, et al (2003) Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. J Immunol 171(2):717–725

    PubMed  CAS  Google Scholar 

  22. Matsushima H, et al (2004) TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. J Immunol 173(1):531–541

    PubMed  CAS  Google Scholar 

  23. Norian LA, Allen PM (2004) No intrinsic deficiencies in CD8+ T cell-mediated antitumor immunity with aging. J Immunol 173:835–844

    PubMed  CAS  Google Scholar 

  24. Osada T, et al (2006) Dendritic cell-based immunotherapy. Rev Immunol 25:377–413

    Article  CAS  Google Scholar 

  25. Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036

    Article  PubMed  CAS  Google Scholar 

  26. Plowden JM, et al (2004) Impaired antigen-induced CD8+ T cell clonal expansion in aging is due to defects in antigen presenting cell function. Cell Immunol 229:86–92

    Article  PubMed  CAS  Google Scholar 

  27. Renshaw M, et al (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169:4697–4701

    PubMed  CAS  Google Scholar 

  28. Rovero S, et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. Infect Immun 72:2810–2816

    Google Scholar 

  29. Salem ML, et al (2005) Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother 28(3):220–228

    Article  PubMed  CAS  Google Scholar 

  30. Sandmand M, et al (2002) Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans? Clin Exp Immunol 127(1):107–114

    Article  PubMed  CAS  Google Scholar 

  31. Saurwein-Teissl M, Romani N, Grubeck-Loebenstein B (2000) Dendritic cells in old age neglected by gerontology? Mech Ageing Dev 121:123–130

    Article  PubMed  CAS  Google Scholar 

  32. Sharma S, Dominguez AL, Lustgarten J (2006) Aging affect the anti-tumor potential of dendritic cell vaccination, but it can be overcome by co-stimulation with anti-OX40 or anti-4-1BB. Exp Gerontol 41:78–84

    Article  PubMed  CAS  Google Scholar 

  33. Sharma S, Dominguez AL, Lustgarten J (2006) High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol 177(12):8348–8355

    PubMed  CAS  Google Scholar 

  34. Sun J, et al (2005) TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development. J Immunol 174(2):742–751

    PubMed  CAS  Google Scholar 

  35. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    Article  PubMed  CAS  Google Scholar 

  36. Tamir A, et al (2007) Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors. Cancer Immunol Immunother (in press). doi:10.1007/s00262-007-0299-y

  37. Tan T, Coussens L (2007) Humoral immunity, inflammation and cancer. Curr Opin Immunol 19(2):209–216

    Article  PubMed  CAS  Google Scholar 

  38. Tortorella C, et al (2002) APC-dependent impairment of T cell proliferation in aging: role of CD28- and IL-12/IL-15-mediated signaling. Mech Ageing Dev 123:1389–1402

    Article  PubMed  CAS  Google Scholar 

  39. Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7(3):179–190

    Article  PubMed  CAS  Google Scholar 

  40. Vargas A, et al (2003) Age-dependent changes in thymic macrophages and dendritic cells. Microsc Res Tech 62:501–507

    Article  Google Scholar 

  41. Xu D, Liu H, Komai-Koma M (2004) Direct and indirect role of Toll-like receptors in T cell mediated immunity. Cell Mol Immunol 1(4):239–246

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by Grant CA78579 and AG028751 (to J. L.) from the National Institutes of Health.

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Authors and Affiliations

  1. Cancer Center Scottsdale, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA

    Sanjay Sharma, Ana Lucia Dominguez, Dominique B. Hoelzinger & Joseph Lustgarten

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  1. Sanjay Sharma
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  2. Ana Lucia Dominguez
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  3. Dominique B. Hoelzinger
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  4. Joseph Lustgarten
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Correspondence to Joseph Lustgarten.

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Sharma, S., Dominguez, A.L., Hoelzinger, D.B. et al. CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol Immunother 57, 549–561 (2008). https://doi.org/10.1007/s00262-007-0393-1

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