Critical Reviews in Oncology / Hematology
Volume 74, Issue 1 , Pages 40-60 , April 2010

The role of immunity in elderly cancer

  • Lucia Malaguarnera

      Affiliations

    • Department of Biomedical Sciences, University of Catania, Italy
  • ,
  • Erika Cristaldi

      Affiliations

    • Department of Senescence, Urological and Neurological Sciences, University of Catania, Italy
  • ,
  • Mariano Malaguarnera

      Affiliations

    • Department of Senescence, Urological and Neurological Sciences, University of Catania, Italy
    • Corresponding Author InformationCorresponding author at: Department of Senescence, Urological and Neurological Sciences, Azienda Ospedaliera Cannizzaro, via Messina 829, 95124 Catania, Italy. Tel.: +39 095 7262008; fax: +39 095 7262011.

,Accepted 5 June 2009.

References 

  1. National Cancer Institute - SEER Cancer Statistics Review 1975–2005.
  2. Malaguarnera M, Laurino A, Di Mauro S, Motta M, Di Fazio I, Maugeri D. The comorbidities of elderly oncologic patients. Arch Gerontol Geriatr. 2000;30:237–244
  3. Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing. Nature. 2007;448:767–774
  4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70
  5. Murasko DM, Nelson BJ, Silver R, Matour D, Kaye D. Immunologic response in an elderly population with a mean age of 85. Am J Med. 1986;81(4):612–618
  6. Franceschi C, Monti D, Barbieri D, et al. Immunosenescence in humans: deterioration or remodelling?. Int Rev Immunol. 1995;12(1):57–74
  7. Sansoni P, Vescovini R, Fagnoni F, et al. The immune system in extreme longevity. Exp Gerontol. 2008;43(2):61–65
  8. Cambier J. Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling. Immunol Rev. 2005;205:5–6
  9. Franceschi C, Bonafe M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci. 2000;908:244–254
  10. Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity ageing and cancer. Immun Ageing. 2008;5:11
  11. Potestio M, Pawelec G, Di Lorenzo G, et al. Age-related changes in the expression of CD95 (APO1/FAS) on blood lymphocytes. Exp Gerontol. 1999;34:659–673
  12. Powers DC. Effect of age on serum immunoglobulin G subclass antibody responses to inactivated influenza virus vaccine. J Med Virol. 1994;43:57–61
  13. Adibzadeh M, Mariani E, Bartoloni C, et al. Lifespans of T lymphocytes. Mech Ageing Dev. 1996;91:145–154
  14. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144–156
  15. Miller JP, Allman D. Linking age-related defects in B lymphopoiesis to the aging of hematopoietic stem cells. Semin Immunol. 2005;17(5):321–329
  16. Nilsson-Ehle H, Swolin B, Westin J. Bone marrow progenitor cell growth and karyotype changes in healthy 88-year-old subjects. Eur J Haematol. 1995;55:14–18
  17. Ogawa T, Kitagawa M, Hirokawa K. Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mech Ageing Dev. 2000;117:57–68
  18. Xing Z, Ryan MA, Daria D, et al. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006;108:2190–2197
  19. Rando TA. Stem cells, ageing and the quest for immortality. Nature. 2006;441(7097):1080–1086
  20. Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004;5:133–139
  21. Cancro MP, Allman DM, Hayes CE, et al. B cell maturation and selection at the marrow-periphery interface. Immunol Res. 1998;17:3–11
  22. Guerrettaz LM, Johnson SA, Cambier JC. Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging. Proc Natl Acad Sci U S A. 2008;105(33):11898–11902
  23. Geiger H, Van Zant G. The aging of lympho-hematopoietic stem cells. Nat Immunol. 2002;3:329–333
  24. Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996;2:1011–1016
  25. Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194–9199
  26. Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443:421–426
  27. Colonna-Romano G, Bulati M, Aquino A, et al. B cell immunosenescence in the elderly and in centenarians. Rejuvenation Res. 2008;11(2):433–439
  28. Franceschi C, Valensis S, Fagnoni S, Barbi C, Bonafe M. Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogenicity and the role of antigenic load. Exp Gerontol. 1999;34:911–921
  29. Colonna-Romano G, Bulati M, Aquino A, et al. B-cell in the aged: CD27, CD5, and CD40 expression. Mech Ageing Dev. 2003;124:389–393
  30. Weksler ME. Changes in the B-cell repertoire with age. Vaccine. 2000;18:1624–1628
  31. Hu A, Ehleiter D, Ben-Yeuda A. Effect of age on the expressed B cell repertoire: role of B cell subsets. Int Immunol. 1993;5:1035–1039
  32. Nicoletti C. Antibody protection in aging: influence of idiotypic repertoire and antibody binding activity to a bacterial antigen. Exp Mol Pathol. 1995;62:99–108
  33. Johnson SA, Rozzo SJ, Cambier JC. Aging-dependent exclusion of antigen inexperienced cells from the peripheral B cell repertoire. J Immunol. 2002;168:5014–5023
  34. Sailey RW, Eun SY, Russell CE, Vogel LA. B cells of aged mice show decreased expansion in response to antigen, but are normal in effector function. Cell Immunol. 2001;214:99
  35. Min H, Montecino-Rodriguez E, Dorshkind K. Effects of aging on the common lymphoid progenitor to Pro-B cell transition. J Immunol. 2006;176:1007–1012
  36. Johnson KM, Owen K, Witte PL. Aging and developmental transitions in the B cell lineage. Int Immunol. 2002;14:1313–1323
  37. Labrie JE, Sah AP, Allman DM, Cancro MP, Gerstein RM. Bone marrow micro-environmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. J Exp Med. 2004;200:411–423
  38. Riley RL, Van der Put E, King AM, Frasca D, Blomberg BB. Deficient B lymphopoiesis in murine senescence: potential roles for dysregulation of E2A, Pax-5, and STAT5. Semin Immunol. 2005;17(5):330–336
  39. Zheng B, Han S, Takahashi Y, Kelsoe G. Immunosenescence and germinal center reaction. Immunol Rev. 1997;160:63–77
  40. Nicoletti C, Yang X, Cerny J. Repertoire diversity of antibody response to bacterial antigens in aged mice. III. Phosphorylcholine antibody from young and aged mice differ in structure and protective activity against infection with Streptococcus pneumoniae. J Immunol. 1993;150:543–549
  41. Yang X, Stedra J, Cerny J. Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centres of aged mice. J Exp Med. 1996;183(3):959–970
  42. Lazuardi L, Jenewein B, Wolf AM, Pfister G, Tzankov A, Grubeck-Loebenstein B. Age-related loss of naïve T cells and dysregulation of T cell/B cell interactions in human lymph nodes. Immunology. 2005;114(1):37–43
  43. Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121:1–14
  44. Koebel CM, Vermi W, Swann JB, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007;450(7171):903–907
  45. Mauro C, Zazzeroni F, Papa S, Bubici C, Franzoso G. The NF-kappaB transcription factor pathway as a therapeutic target in cancer: methods for detection of NF-kappaB activity. Methods Mol Biol. 2009;512:169–207
  46. Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66:1–9
  47. Lai P, Rabinowich H, Crowley-Nowick PA, Bell MC, Mantovani G, Whiteside TL. Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin Cancer Res. 1996;2:161–173
  48. Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992;258(5089):1795–1798
  49. Rabinowich H, Banks M, Reichert TE, Logan TF, Kirkwood JM, Whiteside TL. Expression and activity of signaling molecules in T lymphocytes obtained from patients with metastatic melanoma before and after interleukin 2 therapy. Clin Cancer Res. 1996;2:1263–1274
  50. Rabinowich H, Reichert TE, Kashii Y, Bell MC, Whiteside TL. Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells: implications for altered expression of TCR in tumour-associated lymphocytes. J Clin Invest. 1998;101:2579–2588
  51. Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol. 2001;167:2972–2978
  52. Sheu BC, Lin RH, Ho HN, Huang SC. Down-regulation of CD25 expression on the surface of activated tumor-infiltrating lymphocytes in human cervical carcinoma. Hum Immunol. 1997;56:39–48
  53. Sheu BC, Lien HC, Ho HN, et al. Increased expression and activation of gelatinolytic matrix metalloproteinases is associated with the progression and recurrence of human cervical cancer. Cancer Res. 2003;63:6537–6542
  54. Kolenko V, Wang Q, Riedy MC, et al. Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas. J Immunol. 1997;159:3057–3067
  55. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47
  56. Youssef MM, Symonds P, Ellis IO, Murray JC. EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer. Br J Cancer. 2006;95:735–743
  57. Gastman BR, Johnson DE, Whiteside TL, Rabinowich H. Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events. Blood. 2000;95:2015–2023
  58. Malaguarnera L, Cristaldi E, Vinci M, Malaguarnera M. The role of exercise on the innate immunity of the elderly. Eur Rev Aging Phys Act. 2008;5:43–49
  59. Malaguarnera L, Cristaldi E, Lipari H, Malaguarnera M. Acquired immunity: immunosenescence and physical activity. Eur Rev Aging Phys Act. 2008;5(2):61–68
  60. Gupta S. Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules. Exp Gerontol. 2002;37:293–299
  61. McLeod JD. Apoptotic capability in ageing T cells. Mech Ageing Dev. 2000;121(1-3):151–159
  62. Malaguarnera L, Ferlito L, Di Mauro S, Imbesi RM, Scalia G, Malaguarnera M. Immunosenescence and cancer: a review. Arch Gerontol Geriatr. 2001;32(2):77–93
  63. Norian LA, Allen PM. No intrinsic deficiencies in CD8+ T cell-mediated antitumor immunità with aging. J Immunol. 2004;173:835–844
  64. Effros RB. Long-term immunological memory against viruses. Mech Ageing Dev. 2000;121:161–171
  65. Effros RB. Immune system activity. Handbook of the biology of ageing. 5th ed.. San Diego: Academic Press; 2001;
  66. Beverley PC, Grubeck-Loebenstein B. Is immune senescence reversible?. Vaccine. 2000;18:1721–1724
  67. Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P. Control of homeostasis of CD8 memory T cells by opposing cytokines. Science. 2000;288:675–678
  68. Spaulding C, Guo W, Effros RB. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol. 1999;34:633–644
  69. Krieger NR, Yin DP, Garrison Fathman C. CD4+ but not CD8+ cells are essential for allo-rejection. J Exp Med. 1996;184:2013–2018
  70. Shearer GM. Th1/Th2 changes in aging. Mech Ageing Dev. 1997;94:1–5
  71. Rink L, Cakman I, Kirchner H. Altered cytokine production in the elderly. Mech Ageing Dev. 1998;102:199–209
  72. Wing K, Suri-Payer E, Rudin A. CD4+ CD25+- regulatory T cells from mouse to man. Scand J Immunol. 2005;62(1):1–15
  73. Sakaguchi S, Takahashi T, Yamazaki S, et al. Immunologic self tolerance maintained by T-cell-mediated control of self reactive T cells: implications for autoimmunity and tumor immunity. Microb Infect. 2001;3:911–918
  74. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6(4):353–360
  75. Toda A, Piccirillo CA. Development and function of naturally occurring CD4+ CD25+ regulatory T cells. J Leukoc Biol. 2006;80(3):458–470
  76. Chattopadhyay S, Chakraborty NG, Mukherji B. Regulatory T cells and tumor immunity. Cancer Immunol Immunother. 2005;54:1153–1161
  77. Trzonkowski P, Szmit E, Mysliwska J, Mysliwski A. CD4+ CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans—impact of immunosenescence. Clin Immunol. 2006;119(3):307–316
  78. Colonna-Romano G, Equino A, Bulati M, et al. Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence. Exp Gerontol. 2004;39:1439–1446
  79. Ferrarini M, Ferrero E, Dagna L, Poggi A, Zocchi MR. Human γδ T cells a non redundant system in the immune-surveillance against cancer. Trends Immunol. 2002;23:14–18
  80. Constant P, Davodeau F, Peyrat MA, et al. Stimulation of human gamma delta T cells by non peptidic mycobacterial ligands. Science. 1994;264:267–270
  81. Cipriani B, Borsellino G, Poccia F, et al. Activation of C-C beta-chemokines in human peripheral blood gamma-delta T cells by isopentenyl pyrophosphate and regulation by cytokines. Blood. 2000;95:39–47
  82. Argentati K, Re F, Donnini A, et al. Numerical and functional alterations of circulating gamma delta T lymphocytes in aged people and centenarians. J Leucoc Biol. 2002;72:65–71
  83. Krishnaraj R. Senescence and cytokines modulate the NK cell expression. Mech Ageing Dev. 1997;96:89–101
  84. Borrego F, Alonso MC, Galiani MD, et al. NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol. 1999;34:253–265
  85. Kutza J, Murasko DM. Age-associated decline in IL-2 and IL-12 induction of LAK cell activity of human PBMC samples. Mech Ageing Dev. 1996;90:209–222
  86. Solana R, Mariani E. NK and NK/T cells in human senescence. Vaccine. 2000;18:1613–1620
  87. Rabinowich H, Goses Y, Reshef T, Klajman A. Interleukin- 2 production and activity in aged humans. Mech Ageing Dev. 1985;32:213–226
  88. Bender BS, Chrest FJ, Adler WH. Phenotypic expression of natural killer cell associated membrane antigens and cytolytic function of peripheral blood cells from different aged humans. J Clin Lab Immunol. 1986;21:31–36
  89. Sato T, Fuse A, Kuwata T. Enhancement by IFN of natural cytotoxic activity of lymphocytes from human cord blood and peripheral blood of aged persons. Cell Immunol. 1979;45:458–463
  90. Kutza J, Murasko DM. Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-alpha. Cell Immunol. 1994;155:195–204
  91. Argentati K, Bartozzi B, Bernardini G, Di Stasio G, Provinciali M. Induction of NK cell activity and perforin and Granzyme B expression following continuous culture or short pulse with IL-12 in young and old mice. Eur Cytokine Netw. 2000;11:59–65
  92. Provinciali M, Di Stefano G, Stronati S, Fabris N. Generation of human lymphokine-activated killer cells following an IL-2 pulse in elderly cancer patients. Cytokine. 1998;10(2):132–139
  93. Bykovskaya SN, Abronina IF, Kupriyanova TA, Bubenik J. Down-regulation of LAK cell-mediated cytotoxicity: cancer and ageing. Biomed Pharmacother. 1990;44:333–338
  94. Lipschitz DA, Udupa KB, Milton KY, Thompson CO. Effect of age on hematopoiesis in man. Blood. 1984;63:502–509
  95. Provinciali M, Di Stefano G, Fabris N. Evaluation of LAK cell development in young and old healthy humans. Nat Immun. 1995;14:134–144
  96. Mariani E, Pulsatelli L, Meneghetti A, et al. Different IL-8 production by T and NK lymphocytes in elderly subjects. Mech Ageing Dev. 2001;122:1383–1395
  97. Fabris N, Mocchegiani E, Provinciali M. Plasticity of neuroendocrine-thymus interactions during aging. Exp Gerontol. 1997;32:415–429
  98. Provinciali M, Fabris , Pieri C. Improvement of natural killer cell activity by in vitro active lipids (AL 721) administration in old mice. Mech Ageing Dev. 1990;52:245–254
  99. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 2000;356:1795–1799
  100. Takeuchi H, Maehara Y, Tokunaga E, Koga T, Kakeji Y, Sugimachi K. Ognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis. Am J Gastroenterol. 2001;96:574–578
  101. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?. Trends Immunol. 2002;23(9):445–449
  102. Donnini A, Argentati K, Mancini R, et al. Phenotype antigen-presenting capacity, and migration of antigen-presenting cells in young and old age. Exp Gerontol. 2002;37:1097–1112
  103. Carrard G, Bulteau AL, Petropoulos I, Friguet B. Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol. 2002;34:1461–1474
  104. Mishto M, Santoro A, Bellavista E, Bonafe M, Monti D, Franceschi C. Immunoproteasomes and immunosenescence. Ageing Res Rev. 2003;2:419–432
  105. Meidenbauer N, Zippelius A, Pittet MJ, et al. High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma. Cancer Res. 2004;64(17):6319–6326
  106. Lung TL, Saurwein-Teissl M, Parson W, Schonitzer D, Grubeck-Loebenstein B. Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine. 2000;18:1606–1612
  107. Miller C, Kelsoe G, Han S. Lack of B7-2 expression in the germinal centers of aged mice. Ageing Immunol Infect Dis. 1994;5:249
  108. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–680
  109. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell. 2004;3(4):161–167
  110. Franc NC, White K, Ezekowitz RA. Phagocytosis and development: back to the future. Curr Opin Immunol. 1999;11:47–52
  111. Ohashi K, Burkart V, Flohe S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000;164:558–561
  112. Castle S, Uyemura K, Wong W, Modlin RL, Effros R. Evidence of enhanced type 2 immune response and impaired up-regulation of a type 1 response in frail elderly nursing home residents. Mech Ageing Dev. 1997;94:7–16
  113. Lio D, D’Anna C, Gervasi F, et al. Interleukin-12 release by mitogen-stimulated mononuclear cells in the elderly. Mech Ageing Dev. 1998;102:211–219
  114. Steger MM, Maczek C, Grubeck-Loebenstein B. Morphologically and functionally intact dendritic cells can be derived from the peripheral blood of aged individuals. Clin Exp Immunol. 1996;105:544–550
  115. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994;179:1109–1118
  116. Della Bella S, Bierti L, Presicce P, et al. Peripheral blood dendritic cells and monocyte are differently regulated in elderly. Clin Immunol. 2007;122:220–228
  117. Kiertscher S, Luo J, Dubinett SM, Roth MD. Tumors promote altered maturation and early apoptosis of monocyte-derived dendritic cells. J Immunology. 2000;164:1269–1276
  118. Alberti S, Cevenini E, Ostan R, et al. Age-dependent modifications of type 1 and type 2 cytokines within virgin and memory CD4+T cells in humans. Mech Ageing Dev. 2006;12:560–566
  119. Sadeghi HM, Schnelle JF, Thoma JK, Nishanian P, Fahey JL. Phenotypic and functional characteristics of circulating monocytes of elderly persons. Exp Gerontol. 1999;34:959–970
  120. O’Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K. Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol. 1998;113:213–219
  121. Ahluwalia N, Mastro AM, Ball R, Miles MP, Rajendra R, Handte G. Cytokine production by stimulated mononuclear cells did not change with ageing in apparently healthy, well-nourished women. Mech Ageing Dev. 2001;122:1269–1279
  122. McLachlan JA, Serkin CD, Morrey KM, Bakouche O. Antitumoral properties of aged human monocytes. J Immunol. 1995;154:832–843
  123. Khare V, Sodhi A, Singh SM. Effect of ageing on the tumoricidal functions of murine peritoneal macrophages. Nat Immun. 1996;15:285–294
  124. Herrero C, Marques L, Lloberas J, Celada A. IFNgamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest. 2001;107:485–493
  125. Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S. Cutting edge: impaired Toll-like receptor expression and function in ageing. J Immunol. 2002;169:4697–4701
  126. Provinciali M, Smorlesi A. Immunoprevention and immunotherapy of cancer in ageing. Cancer Immunol Immunother. 2005;54:93–106
  127. Provinciali M, Argentati K, Tibaldi A. Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered 103 to release IL-2 are rejected but do not induce tumor specific immune memory in old mice. Gene Ther. 2000;7:624–632
  128. Chatta GS, Andrews RG, Rodger E, Schrag M, Hammond WP, Dale DC. Hematopoietic progenitors and ageing: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol. 1993;48:M207
  129. Biasi D, Carletto A, Dell’Agnola C, et al. Neutrophil migration, oxidative metabolism, and adhesion in elderly and young subjects. Inflammation. 1996;20:673–681
  130. Butcher SK, Chahal H, Nayak L, et al. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol. 2001;70:881–886
  131. Ponnappan U, Zhong M, Trebilcock GU. Decreased proteasome-mediated degradation in T cells from the elderly: a role in immune senescence. Cell Immunol. 1999;192(2):167–174
  132. Mishto M, Bonafè M, Salvioli S, Olivieri F, Franceschi C. Age dependent impact of LMP polymorphisms on TNFalpha-induced apoptosis in human peripheral blood mononuclear cells. Exp Gerontol. 2002;37(2–3):301–308
  133. Frasca D, Scarpaci S, Barattini P, et al. The DNA repair protein ku is involved in gp130-mediated signal transduction events in PBMC from young but not from elderly subjects. Exp Gerontol. 2002;37(2–3):321–328
  134. Mariani E, Cattini L, Neri S, et al. Simultaneous evaluation of circulating chemokine and cytokine profiles in elderly subjects by multiplex technology: relationship with zinc status. Biogerontology. 2006;7(5–6):449–459
  135. Olivieri F, Bonafè M, Giovagnetti S, et al. In vitro IL-6 production by EBV-immortalized B lymphocytes from young and elderly people genotyped for −174C/G polymorphism in IL-6 gene: a model to study the genetic basis of inflamm-aging. Mech Ageing Dev. 2003;124(4):549–553
  136. Airoldi I, Di Carlo E, Cocco C, et al. Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. Blood. 2005;106:3846–3853
  137. Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J Exp Med. 2002;196:129–134
  138. Street SE, Hayakawa Y, Zhan Y, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. J Exp Med. 2004;199:879–884
  139. Clementi R, Locatelli F, Dupré L, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood. 2005;105:4424–4428
  140. Enzler T, Gillessen S, Manis JP, et al. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med. 2003;197:1213–1219
  141. Coussens LM, Werb Z. Inflammation and cancer. Proc Natl Acad Sci USA. 2002;20:860–867
  142. Shankaran V, Ikeda H, Bruce AT, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Proc Natl Acad Sci USA. 2001;10:1107–1111
  143. Zerafa N, Westwood JA, Cretney E, et al. Cutting edge: TRAIL deficiency accelerates hematological malignancies. J Immunol. 2005;175:5586–5590
  144. Smyth MJ, Thia KY, Street SE, et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med. 2000;192:755–760
  145. Ross OA, Hyland P, Curran MD, et al. Mitochondrial DNA damage in lymphocytes: a role in immunosenescence?. Exp Gerontol. 2002;37(2–3):329–340
  146. Moccheggiani E, Malavolta M. Zinc-gene interaction related to inflammatory/immune response in ageing. Genes Nutr. 2008;3(2):61–75
  147. Silva J, Silva JM, Barradas M, et al. Analysis of the candidate tumor suppressor Ris-1 in primary human breast carcinomas. Mutat Res. 2006;594(1–2):78–85
  148. García-Cao I, García-Cao M, Martín-Caballero J, et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 2002;21(22):6225–6235
  149. Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR. Antioxidants may contribute in the fight against ageing: an in vitro model. Mech Ageing Dev. 2000;121(1–3):217–230
  150. Sourlingas TG, Kypreou KP, Sekeri-Pataryas KE. The effect of the histone deacetylase inhibitor, trichostatin A, on total histone synthesis, H1(0) synthesis and histone H4 acetylation in peripheral blood lymphocytes increases as a function of increasing age: a model study. Exp Gerontol. 2002;37(2–3):341–348
  151. Fulop T, Dupuis G, Fortin C, Douziech N, Larbi A. T cell response in aging: influence of cellular cholesterol modulation. Adv Exp Med Biol. 2006;584:157–169
  152. Fortin CF, Larbi A, Dupuis G, Lesur O, Fülöp T. GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals. Biogerontology. 2007;8(2):173–187
  153. Witkowski JM, Bryl E. Paradoxical age-related cell cycle quickening of human CD4(+) lymphocytes: a role for cyclin D1 and calpain. Exp Gerontol. 2004;39(4):577–585
  154. Motta M, Ferlito L, Malaguarnera L, et al. Alterations of the lymphocytic set-up in elderly patients with cancer. Arch Gerontol Geriatr. 2003;36:7–14
  155. Walker PR, Saas P, Dietrich P-Y. Role of Fas Ligand (CD95L) in immune escape: the tumor cell strikes back. J Immunol. 1997;158:4521–4524
  156. Zhou D, Chrest FJ, Adler W, Munster A, Winchurch RA. Increased production of TGF-beta and IL-6 by aged spleen cells. Immunol Lett. 1993;36:7–11
  157. Goodwin JS, Messner RP. Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70. J Clin Invest. 1979;64:434–439
  158. Chidrawar S, Khan N, Wei W, et al. Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin Exp Immunol. 2009;155:423–432
  159. Zanni F, Vescovini R, Biasini C, et al. Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence. Exp Gerontol. 2003;38:981–987
  160. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117(5):1175–1183
  161. Dinarello CA. The paradox of pro-inflammatory cytokines in cancer. Cancer Metastasis Rev. 2006;25:307–313
  162. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–217
  163. Agarwal A, Verma S, Burra U, Murthy NS, Mohanty NK, Saxena S. Flow cytometric analysis of Th1 and Th2 cytokines in PBMCs as a parameter of immunological dysfunction in patients of superficial transitional cell carcinoma of bladder. Cancer Immunol Immunother. 2006;55(6):734–743
  164. Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th27Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol. 2001;167:2972
  165. Woodworth CD, McMullin E, Iglesias M, Plowman GD. Interleukin 1 alpha and tumor necrosis factor alpha stimulate autocrine amphiregulin expression and proliferation of human papillomavirus-immortalized and carcinoma-derived cervical epithelial cells. Proc Natl Acad Sci USA. 1995;92(7):2840–2844
  166. Arlt A, Vorndamm J, Muerkoster S, et al. Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res. 2002;62(3):910–916
  167. Saijo Y, Tanaka M, Miki M, et al. Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction. J Immunol. 2002;169(1):469–475
  168. Lin EY, Nguyen AV, Russell RG, Pallard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp med. 2001;193:727–740
  169. Mocellin S, Rossi CR, Pilati P, Nitti D. Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev. 2005;16:35–53
  170. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M. Inhibition of NF-kB in cancer cells converts inflammation-induced tumor growth mediated by TNF-α to TRAIL-mediated tumor regression. Cancer Cell. 2004;6:297–305
  171. Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer. 2003;3:276–285
  172. Elgert KD, Alleva DG, Mullins DW. Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol. 1998;64:275–290
  173. Knight B, Yeoh GC, Husk KL, et al. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J Exp Med. 2000;192:1809–1818
  174. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link?. Biochemical Pharmacol. 2006;72:1605–1621
  175. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80:227–236
  176. Belardelli F, Ferrantini M, Proietti E, Kirkwood JM. Interferon α in tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 2002;13:119–134
  177. Biron CA. Interferons α and β as immune regulators—a new look. Immunity. 2001;14:661–664
  178. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765
  179. Hoentjen F, Sartor RB, Ozaki M, Jobin C. STAT3 regulates NF-kB recruitment to the IL-12p40 promoter in dendritic cells. Blood. 2005;105:689–696
  180. Kundu N, Fulton AM. Interleukin-10 inhibits tumor metastasis, down-regulates MHC class I, and enhances NK lysis. Cell Immunol. 1997;180:55–61
  181. Blankenstein T. The role of tumor stroma in the interaction between tumor and immune system. Curr Opin Immunol. 2005;17:180–186
  182. Lech-Maranda E, Bienvenu J, Michallet AS, et al. Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. Eur Cytokine Netw. 2006;17:60–66
  183. Ogden CA, Pound JD, Batth BK, et al. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10–activated macrophages: implications for Burkitt's lymphoma. J. Immunol. 2005;174:3015–3023
  184. Sakamoto T, Saito H, Tatebe S, et al. Interleukin-10 expression significantly correlates with minor CD8+ T cell infiltration and high microvessel density in patients with gastric cancer. Int J Cancer. 2006;118:1909–1914
  185. Mocellin S, Marincola FM, Young HA. Interleukin-10 and the immune response against cancer: a counterpoint. J Leukoc Biol. 2005;78:1043–1051
  186. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev. 2003;3:133–146
  187. Terabe M, Park JM, Berzofsky JA. Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother. 2004;53:79–85
  188. Numasaki M, Watanabe M, Suzuki T, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2–dependent angiogenesis. J Immunol. 2005;175:6177–6189
  189. Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–2727
  190. Kothapalli R, Nyland SB, Kusmartseva I, Bailey RD, McKeown TM, Loughran TP. Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukaemia. Int J Oncol. 2005;26(2):529–535
  191. Hao JS, Shan BE. Immune enhancement and anti-tumour activity of IL-23. Cancer Immunol Immunother. 2006;55:1426–1431
  192. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461–465
  193. Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705
  194. Bazan JF, Bacon KB, Hardiman G. A new class of membrane bound chemokine with a CX3C motif. Nature. 1997;385:640–644
  195. Garcia-Zepeda EA, Combadiere C, Rothenberg ME. Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and non-allrgic inflammation that signals through the CC chemokine receptors (CCR)-2 and 3. J Immunol. 1996;157:5613–5626
  196. Luboshits G, Shina S, Kaplan O. Elevated expression of the CC Chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 1999;59:4681–4687
  197. Mo R, Chen J, Han Y, et al. T cell chemokine receptor expression in aging. J Immunol. 2003;170:895–904
  198. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector function. Nature. 1999;401:708
  199. Wolf M, Albrecht S, Märki C. Proteolytic processing of chemokines: implications in physiological and pathological conditions. Int J Biochem Cell Biol. 2008;40(6-7):1185–1198
  200. Mule JJ, Custer M, Averbook B, et al. RANTES secretion by gene-modified tumor cells results in loss of tumorigenicity in vivo: role of immune cell subpopulations. Hum Gene Ther. 1996;7:1545–1553
  201. Tang KF, Tan SY, Chan SH, et al. A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma: implication for the intense tumor infiltration by T lymphocytes and macrophages. Hum Pathol. 2001;32:42–49
  202. Negus RP, Stamp GW, Hadley J, Balkwill FR. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of CC chemokines. Am J Pathol. 1997;150:1723–1734
  203. Pertl U, Luster AD, Varki NM, et al. IFN-γ inducible protein-10 is essential for the generation of a protective tumor-specific CD8 T cell response induced by single-chain IL-12 gene therapy. J Immunol. 2001;166:6944–6951
  204. Cairns CM, Gordon JR, Li F, Baca-Estrada ME, Moyana T, Xiang J. Lymphotactin expression by engineered myeloma cells drives tumor regression: mediation by CD4(+) and CD8(+) T cells and neutrophils expressing XCR1 receptor. J Immunol. 2001;167:57–65
  205. Irmiger-Finger I. Science of cancer and aging. J Clin Oncol. 2007;25:1844–1851
  206. Warner HR, Hodes RJ, Pocinki K. What does cell death have to do with aging?. J Am Gertiatr Soc. 1997;45:1140–1146
  207. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorogenesis: a link between cancer and aging. Proc Natl Acad Sci USA. 2001;98:12072–12077
  208. Hockenbery D, Nunez C, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348:334–336

PII: S1040-8428(09)00122-X

doi: 10.1016/j.critrevonc.2009.06.002

Critical Reviews in Oncology / Hematology
Volume 74, Issue 1 , Pages 40-60 , April 2010