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Cancer, aging and immunotherapy: lessons learned from animal models

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Abstract

Aging of the immune system is associated with a dramatic reduction in responsiveness as well as functional dysregulation. This deterioration of immune function with advancing age is associated with an increased incidence of cancer. Although there is a plethora of reports evaluating the effect of immunotherapy in stimulating antitumor immune responses, the majority of these studies do not pay attention to the effect aging has on the immune system. Studies from our group and others indicate that immunotherapies could be effective in the young, are not necessarily effective in the old. To optimally stimulate an antitumor immune response in the old, it is necessary to (1) identify and understand the intrinsic defects of the old immune system and (2) use relevant models that closely reflect those of cancer patients, where self-tolerance and aging are present simultaneously. The present review summarizes some defects found in the old immune system affecting the activation of antitumor immune responses, the strategies used to activate stronger antitumor immune response in the old and the use of a tolerant animal tumor model to target a self-tumor antigen for the optimization of immunotherapeutic interventions in the old.

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References

  1. Aw D, Silva A, Palmer D (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120:435–446

    Article  PubMed  CAS  Google Scholar 

  2. Bansal-Pakala P, Croft M (2002) Defective T cell priming associated with aging can be rescued by signaling through 4-1BB (CD137). J Immunol 169:5005–5009

    PubMed  Google Scholar 

  3. Bloom E, Umehara H, Bleackley R, Okumura K, Mostowski H, Babbitt J (1990) Age-related decrement in cytotoxic T lymphocyte (CTL) activity is associated with decreased levels of mRNA encoded by two CTL-associated serine esterase genes and the perforin gene in mice. Eur J Immunol 20:2309

    Article  PubMed  CAS  Google Scholar 

  4. Boehmer E, Goral J, Faunce D, Kovacs E (2004) Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75:342–349

    Article  PubMed  CAS  Google Scholar 

  5. Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner E, Werner-Felmayer G, Weiss H, Gobel G et al (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12:1144–1151

    Article  PubMed  CAS  Google Scholar 

  6. Bullock T, Yagita H (2005) Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J Immunol 174:710–717

    PubMed  CAS  Google Scholar 

  7. Bunt S, Yang L, Sinha P, Clements V, Leips J, Ostrand-Rosenberg S (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 67:10019–10026

    Article  PubMed  CAS  Google Scholar 

  8. Butte M, Keir M, Phamduy T, Sharpe A, Freeman G (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–122

    Article  PubMed  CAS  Google Scholar 

  9. Clambey E, van Dyk L, Kappler J, Marrack P (2005) Non-malignant clonal expansions of CD8+ memory T cells in aged individuals. Immunol Rev 205:170–189

    Article  PubMed  CAS  Google Scholar 

  10. Cuadros C, Dominguez A, Frost G, Borgstrom P, Lustgarten J (2003) Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice. Cancer Res 63:5895

    PubMed  CAS  Google Scholar 

  11. Cuadros C, Dominguez A, Lollini P, Croft M, Mittler R, Borgstrom P, Lustgarten J (2005) Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer 116:934–943

    Article  PubMed  CAS  Google Scholar 

  12. De Smedt T, Smith JH, Baum P, Fanslow W, Butz E, Maliszewski C (2002) Ox40 costimulation enhances the development of T cell responses induced by dendritic cells in vivo. J Immunol 168:661–670

    PubMed  Google Scholar 

  13. Dominguez A, Lustgarten J (2008) Implications of aging and self-tolerance on the generation of immune and antitumor immune responses. Cancer Res 68:5423–5431

    Article  PubMed  CAS  Google Scholar 

  14. Engwerda C, Fox B, Handwerger B (1996) Cytokine production by T lymphocytes from young and aged mice. J Immunol 156:3621

    PubMed  CAS  Google Scholar 

  15. Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M, Mellor A, Munn D, Antonia S (2002) Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer 101:151–155

    Article  PubMed  CAS  Google Scholar 

  16. Fulop T, Larbi A, Douziech N, Levesque I, Varin A, Herbein G (2006) Cytokine receptor signalling and aging. Mech Ageing Dev 127:526–537

    Article  PubMed  CAS  Google Scholar 

  17. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone D (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150

    PubMed  CAS  Google Scholar 

  18. Gajewski T, Meng Y, Blank C, Brown I, Kacha A, Kline J, Harlin H (2006) Immune resistance orchestrated by the tumor microenvironment. Immunol Rev 213:131–145

    Article  PubMed  CAS  Google Scholar 

  19. Gallimore A, Godkin A (2008) Regulatory T cells and tumour immunity—observations in mice and men. Immunology 123:157–163

    PubMed  CAS  Google Scholar 

  20. Geiger T, Gooding L, Flavell R (1992) T-cell responsiveness to an oncogenic peripheral protein and spontaneous autoimmunity in transgenic mice. Proc Natl Acad Sci USA 89:2985

    Article  PubMed  CAS  Google Scholar 

  21. Goldrath A, Bevan M (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402:255

    Article  PubMed  CAS  Google Scholar 

  22. Gramaglia I, Weinberg A, Lemon M, Croft M (1998) Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol 15:445

    Google Scholar 

  23. Gravekamp C, Sypniewska R, Gauntt S, Tarango M, Price P, Reddick R (2004) Behavior of metastatic and nonmetastatic breast tumors in old mice. Exp Biol Med (Maywood) 229:665–675

    CAS  Google Scholar 

  24. Green E, Gorelik L, McGregor C, Tran E, Flavell R (2003) CD4+ CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta–TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci USA 100:10878–10883

    Article  PubMed  CAS  Google Scholar 

  25. Greenwald R, Freeman G, Sharpe A (2005) The B7 family revisited. Annu Rev Immunol 23:515–548

    Article  PubMed  CAS  Google Scholar 

  26. Gregg R, Smith C, Clark F, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss P (2005) The number of human peripheral blood CD4+ CD25 high regulatory T cells increases with age. Clin Exp Immunol 140:540–546

    Article  PubMed  CAS  Google Scholar 

  27. Grizzle W, Xu X, Zhang S, Stockard C, Liu C, Yu S, Wang J, Mountz J, Zhang H (2007) Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytoxicity in recombinant inbred B × D12 mice. Mech Ageing Dev 128:672–680

    Article  PubMed  CAS  Google Scholar 

  28. Grubeck-Loebenstein B (1995) Changes in the aging immune system. Biologicals 25:205–208

    Article  Google Scholar 

  29. Guy C, Webster M, Schaller M, Parsons T, Cardiff R, Muller W (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89:10578

    Article  PubMed  CAS  Google Scholar 

  30. 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 

  31. Hobbs M, Weigle W, Noonan D et al (1993) Patterns of cytokine gene expression by CD4+ T cells from young and old mice. J Immunol 150:3602–3614

    PubMed  CAS  Google Scholar 

  32. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  33. Hou D, Muller A, Sharma M, DuHadaway J, Banerjee T, Johnson M, Mellor A, Prendergast G, Munn D (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67:792–801

    Article  PubMed  CAS  Google Scholar 

  34. Huang B, Pan P, Li Q, Sato A, Levy D, Bromberg J, Divino C, Chen S (2006) Gr-1+ CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66:1123–1131

    Article  PubMed  CAS  Google Scholar 

  35. Huang H, Patel D, Manton K (2005) The immune system in aging: roles of cytokines, T cells and NK cells. Front Biosci 10:192–215

    Article  PubMed  CAS  Google Scholar 

  36. Hurwitz A, Kwon E, van Elsas A (2000) Costimulatory wars: the tumor menace. Curr Opin Immunol 12:589

    Article  PubMed  CAS  Google Scholar 

  37. Ino K, Yoshida N, Kajiyama H, Shibata K, Yamamoto E, Kidokoro K, Takahashi N, Terauchi M, Nawa A, Nomura S et al (2006) Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br J Cancer 95:1555–1561

    Article  PubMed  CAS  Google Scholar 

  38. Janeway C Jr, Dianzani U, Portoles P et al (1989) Cross-linking and conformational change in T-cell receptors: role in activation and in repertoire selection. Cold Spring Harb Symp Quant Biol 54:657–666

    PubMed  CAS  Google Scholar 

  39. 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 

  40. Kawarada Y, Ganss R, Garbi N, Sacher T, Arnold B, Hammerling G (2001) NK- and CD8(+) T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J Immunol 167:5247–5253

    PubMed  CAS  Google Scholar 

  41. Kovaiou R, Herndler-Brandstetter D, Grubeck-Loebenstein B (2007) Age-related changes in immunity: implications for vaccination in the elderly. Expert Rev Mol Med 9:1–17

    Article  PubMed  Google Scholar 

  42. Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zhou W (2007) Relationship between B7–H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 67:8900–8905

    Article  PubMed  CAS  Google Scholar 

  43. Kusmartsev S, Nagaraj S, Gabrilovich D (2005) Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 175:4583–4592

    PubMed  CAS  Google Scholar 

  44. Lages C, Suffia I, Velilla P, Huang B, Warshaw G, Hildeman D, Belkaid Y, Chougnet C (2008) Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 181:1835–1848

    PubMed  CAS  Google Scholar 

  45. Latchman Y, Liang S, Wu Y, Chernova T, Sobel R, Klemm M, Kuchroo V, Freeman G, Sharpe A (2004) PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA 101:10691–10696

    Article  PubMed  CAS  Google Scholar 

  46. Li Q, Pan P, Gu P, Xu D, Chen S (2004) Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res 64:1130–1139

    Article  PubMed  CAS  Google Scholar 

  47. Li Y, McGowan P, Hellstrom I, Hellstrom K, Chen L (1994) Costimulation of tumor-reactive CD4+ and CD8+ T lymphocytes by B7, a natural ligand for CD28, can be used to treat established mouse melanoma. J Immunol 153:421

    PubMed  CAS  Google Scholar 

  48. Lin Y, Chen C, Nakano T, Goto S, Kao Y, Hsu L, Lai C, Jawan B, Cheng Y, Yateno C, Yoshizato K (2008) Immunological role of indoleamine 2,3-dioxygenase in rat liver allograft rejection and tolerance. J Gastroenterol Hepatol 23:e243–e250

    Article  PubMed  CAS  Google Scholar 

  49. Lizee G, Radvanyi L, Overwijk W, Hwu P (2006) Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res 12:4794–4803

    Article  PubMed  CAS  Google Scholar 

  50. Luo L, Chapoval A, Flies D, Zhu G, Hirano F, Wang S, Lau J, Dong H, Tamada K, Flies A et al (2004) B7–H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 173:5445–5450

    PubMed  CAS  Google Scholar 

  51. Lustgarten J, Dominguez A, Cuadros C (2004) The CD8+ T cell repertoire against Her-2/neu antigens in neu transgenic mice is of low avidity with antitumor activity. Eur J Immunol 34:752

    Article  PubMed  CAS  Google Scholar 

  52. Lustgarten J, Dominguez A, Pinilla C (2006) Identification of cross-reactive peptides using combinatorial libraries circumvents tolerance against Her-2/neu-immunodominant epitope. J Immunol 176:1796

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  54. Lustgarten J, Theobald M, Labadie C, LaFace D, Peterson P, Disis M, Cheever M, Sherman LA (1997) Identification of Her-2/Neu CTL epitopes using double transgenic mice expressing HLA-A2.1 and human CD.8. Hum Immunol 52:109

    Article  PubMed  CAS  Google Scholar 

  55. Malaguarnera L, Ferlito L, Imbesi R et al (2001) Immunosenescence: a review. Arch Gerontol Geriatr 32:1–14

    Article  PubMed  CAS  Google Scholar 

  56. Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V (2008) Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179

    Article  PubMed  CAS  Google Scholar 

  57. McElhaney J, Meneilly G, Lechelt K, Bleackley R (1994) Split-virus influenza vaccines: do they provide adequate immunity in the elderly? J Gerontol 49:M37–M43

    PubMed  CAS  Google Scholar 

  58. Miller R (1991) Gerenotology as oncology. Research on again as the key to the understanding of cancer. Cancer 68:2496–2501

    Article  PubMed  CAS  Google Scholar 

  59. Miyara M, Sakaguchi S (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13:108–116

    Article  PubMed  CAS  Google Scholar 

  60. Morel Y, Truneh A, Sweet R, Olive D, Costello R (2001) The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 167:2479

    PubMed  CAS  Google Scholar 

  61. Muller W, Sinn E, Pattengale P, Wallace R, Leder P (1988) Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54:105

    Article  PubMed  CAS  Google Scholar 

  62. Munn D, Mellor A (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154

    Article  PubMed  CAS  Google Scholar 

  63. Munn D, Zhou M, Attwood J, Bondarev I, Conway S, Marshall B, Brown C, Mellor A (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193

    Article  PubMed  CAS  Google Scholar 

  64. Nagaraj S, Gabrilovich D (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68:2561–2563

    Article  PubMed  CAS  Google Scholar 

  65. Nishioka T, Shimizu J, Iida R, Yamazaki S, Sakaguchi S (2006) CD4+ CD25+ Foxp3+ T cells and CD4+ CD25-Foxp3+ T cells in aged mice. J Immunol 176:6586–6593

    PubMed  CAS  Google Scholar 

  66. Paganelli R, Scala E, Quinti I, Ansotegui I (1994) Humoral immunity in aging. Aging 6:143

    PubMed  CAS  Google Scholar 

  67. Patriarca P (1994) A randomized controlled trial of influenza vaccine in the elderly. Scientific scrutiny and ethical responsibility. JAMA 272:1700–1701

    Article  PubMed  CAS  Google Scholar 

  68. Pawelec G (2006) Immunity and ageing in man. Exp Gerontol 41:1239–1242

    Article  PubMed  CAS  Google Scholar 

  69. Pertovaara M, Hasan T, Raitala A, Oja S, Yli-Kerttula U, Korpela M, Hurme M (2007) Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season. Clin Exp Immunol 150:274–278

    PubMed  CAS  Google Scholar 

  70. Piccirillo C, Shevach E (2001) Cutting edge: control of CD8+ T cell activation by CD4+ CD25+ immunoregulatory cells. J Immunol 167:1137–1140

    PubMed  CAS  Google Scholar 

  71. Prilliman K, Lemmens E, Palioungas G, Wolfe T, Allison J, Sharpe A, Schoenberger S (2002) Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL. J Immunol 169:4094

    PubMed  CAS  Google Scholar 

  72. Propper D, Chao D, Braybrooke J, Bahl P, Thavasu P, Balkwill F, Turley H, Dobbs N, Gatter K, Talbot D et al (2003) Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma. Clin Cancer Res 9:84–92

    PubMed  CAS  Google Scholar 

  73. Provinciali M, Argentati K, Tibaldi A (2000) Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice. Gene Ther 7:624–632

    Article  PubMed  CAS  Google Scholar 

  74. Provinciali M, Smorlesi A, Donnini A, Bartozzi B, Amici A (2003) Low effectiveness of DNA vaccination against HER-2/neu in ageing. Vaccine 21:843–848

    Article  PubMed  CAS  Google Scholar 

  75. Raes G, Van Ginderachter J, Liu Y, Brys L, Thielemans K, De Baetselier P, Geldhof A (1998) Active antitumor immunotherapy, with or without B7-mediated costimulation, increases tumor progression in an immunogenic murine T cell lymphoma model. Cancer Immunol Immunother 45:257

    Article  PubMed  CAS  Google Scholar 

  76. Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169:4697–4701

    PubMed  CAS  Google Scholar 

  77. Rodriguez P, Ochoa A (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191

    Article  PubMed  CAS  Google Scholar 

  78. Rogers P, Song J, Gramaglia I, Killeen N, Croft M (2001) OX40 promotes Bcl-xl and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15:445

    Article  PubMed  CAS  Google Scholar 

  79. Sadighi Akha A, Miller R (2005) Signal transduction in the aging immune system. Curr Opin Immunol 17:486–491

    Article  PubMed  CAS  Google Scholar 

  80. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  PubMed  CAS  Google Scholar 

  81. Salem M, Kadima A, Cole D, Gillanders W (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 28:220–228

    Article  PubMed  CAS  Google Scholar 

  82. Samy E, Parker L, Sharp C, Tung K (2005) Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+ CD25+ regulatory T cells in the regional lymph node. J Exp Med 202:771

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  84. Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65

    Article  PubMed  CAS  Google Scholar 

  85. Sharma S, Dominguez A, Hoelzinger D, Lustgarten J (2008) 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

    Article  PubMed  CAS  Google Scholar 

  86. Sharma S, Dominguez A, 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 

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

    PubMed  CAS  Google Scholar 

  88. Solana R, Pawelec G (1998) Molecular and cellular basis of immunosenescence. Mech Ageing Dev 102:115–129

    Article  PubMed  CAS  Google Scholar 

  89. Song I, Kim Y, Chopra R et al (1993) Age-related effects in T cell activation and proliferation. Exp Gerontol 28:313

    Article  PubMed  CAS  Google Scholar 

  90. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson J, Whiteside T (2007) A unique subset of CD4+ CD25 high Foxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res 13:4345–4354

    Article  PubMed  CAS  Google Scholar 

  91. Subudhi S, Zhou P, Yerian L, Chin R, Lo J, Anders R, Sun Y, Chen L, Wang Y, Alegre M, Fu Y (2004) Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J Clin Invest 113:694–700

    PubMed  CAS  Google Scholar 

  92. Suri-Payer E, Amar A, Thornton A, Shevach E (1998) CD4+ CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol 160:1212

    PubMed  CAS  Google Scholar 

  93. Takashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S (1998) Immunologic self-tolerance maintained by CD25+ CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  95. Talmadge J (2007) Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res 13:5243–5248

    Article  PubMed  CAS  Google Scholar 

  96. Targonoski P, Jacobson R, Poland G (2007) Immunosenescence: role and measurement in influence vaccine response among the elderly. Vaccine 25:3066–3069

    Article  CAS  Google Scholar 

  97. Taubb D, Longo D (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93

    Article  Google Scholar 

  98. Thoman M (1997) Effects of the aged microenvironment on CD4+ T cell maturation. Mech Ageing Dev 96:75–88

    Article  PubMed  CAS  Google Scholar 

  99. Thoman M, Weigle W (1982) Cell-mediated immunity in aged mice: an underlying lesion in IL 2 synthesis. J Immunol 128:2358–2361

    PubMed  CAS  Google Scholar 

  100. Thompson R, Dong H, Kwon E (2007) Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin Cancer Res 13:709s–715s

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  102. Tsushima F, Yao S, Shin T, Flies A, Flies S, Xu H, Tamada K, Pardoll D, Chen L (2007) Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 110:180–185

    Article  PubMed  CAS  Google Scholar 

  103. van Duin D, Shaw A (2007) Toll-like receptors in older adults. J Am Geriatr Soc 55:1438–1444

    Article  PubMed  Google Scholar 

  104. Watanabe S, Deguchi K, Zheng R, Tamai H, Wang L, Cohen P, Shu S (2008) Tumor-induced CD11b+ Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J Immunol 181:3291–3300

    PubMed  CAS  Google Scholar 

  105. Weatherill A, Maxwell J, Takahashi C, Weinberg A, Vella A (2001) OX40 ligation enhances cell cycle turnover of Ag-activated CD4 T cells in vivo. Cell Immunol 209:63

    Article  PubMed  CAS  Google Scholar 

  106. Weinberg A, Rivera M, Prell R, Morris A, Ramstad T, Vetto J, Urba W, Alvord G, Bunce C, Shields J (2000) Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 164:2160

    PubMed  CAS  Google Scholar 

  107. Yancik R (1997) Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 80:1273–1283

    Article  PubMed  CAS  Google Scholar 

  108. Yancik R (1997) Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 80:1273–1283

    Article  PubMed  CAS  Google Scholar 

  109. Yang Y, Huang C, Huang X, Pardoll D (2004) Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5:508–515

    Article  PubMed  CAS  Google Scholar 

  110. Young M, Petruzzelli G, Kolesiak K, Achille N, Lathers D, Gabrilovich D (2001) Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells. Hum Immunol 62:332

    Article  PubMed  CAS  Google Scholar 

  111. Zang X, Allison J (2007) The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13:5271–5279

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Grant CA78579 and AG028751 from the National Institutes of Health and the American Federation for Aging Research (AFAR).

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  1. Department of Immunology, Mayo Clinic Arizona, Mayo Clinic College of Medicine, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA

    Joseph Lustgarten

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Correspondence to Joseph Lustgarten.

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This article is part of the symposium in writing on "Impact of Ageing on Cancer Immunity and Immunotherapy".

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Lustgarten, J. Cancer, aging and immunotherapy: lessons learned from animal models. Cancer Immunol Immunother 58, 1979–1989 (2009). https://doi.org/10.1007/s00262-009-0677-8

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