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The aging immune system and its relationship with cancer

    Anthony D Foster

    National Cancer Institute (NCI), Experimental Transplantation & Immunology Branch (ETIB), 10 Center Dr. 10 CRC, 3-3330 Bethesda, MD 20814, USA

    ,
    Amogh Sivarapatna

    National Cancer Institute (NCI), Experimental Transplantation & Immunology Branch (ETIB), 10 Center Dr. 10 CRC, 3-3330 Bethesda, MD 20814, USA

    &
    Published Online:https://doi.org/10.2217/ahe.11.56

    The incidence of most common cancers increases with age. This occurs in association with, and is possibly caused by a decline in immune function, termed immune senescence. Although the size of the T-cell compartment is quantitatively maintained into older age, several deleterious changes (including significant changes to T-cell subsets) occur over time that significantly impair immunity. This article highlights some of the recent findings regarding the aging immune system, with an emphasis on the T-cell compartment and its role in cancer.

    Papers of special note have been highlighted as: • of interest •• of considerable interest

    Bibliography

    • Fulop T, Kotb R, Fortin CF, Pawelec G, De Angelis F, Larbi A. Potential role of immunosenescence in cancer development. Ann. NY Acad. Sci.1197,158–165 (2010).
    • Hakim FT, Flomerfelt FA, Boyiadzis M, Gress RE. Aging, immunity and cancer. Curr. Opin. Immunol.16(2),151–156 (2004).
    • Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens70(3),179–189 (2007).
    • Sportès C, Hakim FT. Aging, immunity and cancer. In: Handbook on Immunosenescence: Basic Understanding and Clinical Applications. Fulop T, Franceschi C, Hirokawa K, Pawelec G (Eds). Springer, Berlin, Germany (2009).
    • Schultzel M, Saltzstein SL, Downs TM, Shimasaki S, Sanders C, Sadler GR. Late age (85 years or older) peak incidence of bladder cancer. J. Urol.179(4),1302–1305; discussion 1305–1306 (2008).
    • Candore G, Balistreri CR, Listi F et al. Immunogenetics, gender, and longevity. Ann. NY Acad. Sci.1089,516–537 (2006).
    • Derhovanessian E, Maier AB, Beck R et al. Hallmark features of immunosenescence are absent in familial longevity. J. Immunol.185(8),4618–4624 (2010).
    • Arranz L, Caamano JH, Lord JM, De la Fuente M. Preserved immune functions and controlled leukocyte oxidative stress in naturally long-lived mice: possible role of nuclear factor κB. J. Gerontol. A Biol. Sci. Med. Sci.65(9),941–950 (2010).
    • Arranz L, Lord JM, De la Fuente M. Preserved ex vivo inflammatory status and cytokine responses in naturally long-lived mice. Age (Dordr.)32(4),451–466 (2010).
    • 10  Schreiber TH, Podack ER. A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas. Br. J. Cancer101(3),381–386 (2009).
    • 11  Bedel R, Thiery-Vuillemin A, Grandclement C et al. Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res.71(5),1615–1626 (2011).
    • 12  Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature393(6684),474–478 (1998).
    • 13  Bourgeois C, Rocha B, Tanchot C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science297(5589),2060–2063 (2002).
    • 14  Matsui S, Ahlers JD, Vortmeyer AO et al. A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL. J. Immunol.163(1),184–193 (1999).
    • 15  Gerner MY, Casey KA, Mescher MF. Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses. J. Immunol.181(1),155–164 (2008).
    • 16  Corthay A, Skovseth DK, Lundin KU et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity22(3),371–383 (2005).
    • 17  Corthay A, Lundin KU, Lorvik KB, Hofgaard PO, Bogen B. Secretion of tumor-specific antigen by myeloma cells is required for cancer immunosurveillance by CD4+ T cells. Cancer Res.69(14),5901–5907 (2009).
    • 18  Levitsky HI, Lazenby A, Hayashi RJ, Pardoll DM. In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression. J. Exp. Med.179(4),1215–1224 (1994).
    • 19  Bogen B, Munthe L, Sollien A et al. Naive CD4+ T cells confer idiotype-specific tumor resistance in the absence of antibodies. Eur. J. Immunol.25(11),3079–3086 (1995).
    • 20  Haabeth OA, Lorvik KB, Hammarstrom C et al. Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nat. Comm.2,240 (2011).
    • 21  Nakamura H, Saji H, Ogata A et al. Immunologic parameters as significant prognostic factors in lung cancer. Lung Cancer37(2),161–169 (2002).
    • 22  Unitt E, Marshall A, Gelson W et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J. Hepatol.45(2),246–253 (2006).
    • 23  Vella LA, Yu M, Fuhrmann SR, El-Amine M, Epperson DE, Finn OJ. Healthy individuals have T-cell and antibody responses to the tumor antigen cyclin B1 that when elicited in mice protect from cancer. Proc. Natl Acad. Sci. USA106(33),14010–14015 (2009).
    • 24  Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature450(7171),903–907 (2007).
    • 25  Engel AM, Svane IM, Rygaard J, Werdelin O. MCA sarcomas induced in SCID mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice. Scand. J. Immunol.45(5),463–470 (1997).
    • 26  Shankaran V, Ikeda H, Bruce AT et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature410(6832),1107–1111 (2001).
    • 27  Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Ann. Rev. Immunol.18,529–560 (2000).
    • 28  Seddon B, Tomlinson P, Zamoyska R. Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat. Immunol.4(7),680–686 (2003).
    • 29  Surh CD, Boyman O, Purton JF, Sprent J. Homeostasis of memory T cells. Immunol. Rev.211,154–163 (2006).
    • 30  Ivory K, Martin R, Hughes DA. Significant presence of terminally differentiated T cells and altered NF-κB and I-κBα interactions in healthy ageing. Exp. Gerontol.39(4),567–576 (2004).
    • 31  Ouyang Q, Wagner WM, Wikby A et al. Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J. Clin. Immunol.23(4),247–257 (2003).
    • 32  Arnold CR, Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-Loebenstein B. Gain and loss of T cell subsets in old age – age-related reshaping of the T cell repertoire. J. Clin. Immunol.31(2),137–146 (2011).
    • 33  Sempowski GD, Gooding ME, Liao HX, Le PT, Haynes BF. T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol. Immunol.38(11),841–848 (2001).
    • 34  Kilpatrick RD, Rickabaugh T, Hultin LE et al. Homeostasis of the naive CD4+ T cell compartment during aging. J. Immunol.180(3),1499–1507 (2008).
    • 35  Globerson A, Effros RB. Ageing of lymphocytes and lymphocytes in the aged. Immunol. Today21(10),515–521 (2000).
    • 36  Bouree P. Immunity and immunization in elderly. Pathol. Biol. (Paris)51(10),581–585 (2003).
    • 37  Kang I, Hong MS, Nolasco H et al. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. J. Immunol.173(1),673–681 (2004).
    • 38  Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J. Exp. Med.200(12),1613–1622 (2004).
    • 39  Haynes L, Linton PJ, Eaton SM, Tonkonogy SL, Swain SL. Interleukin 2, but not other common γ chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J. Exp. Med.190(7),1013–1024 (1999).
    • 40  Eaton SM, Maue AC, Swain SL, Haynes L. Bone marrow precursor cells from aged mice generate CD4 T cells that function well in primary and memory responses. J. Immunol.181(7),4825–4831 (2008).•• Demonstrates that memory T cells formed from aged bone marrow precursor cells transferred into young hosts function normally. This supports T-cell-extrinsic factors in age-associated dysfunction.
    • 41  Yehuda AB, Friedman G, Wirtheim E, Abel L, Globerson A. Checkpoints in thymocytopoiesis in aging: expression of the recombination activating genes RAG-1 and RAG-2. Mech. Ageing Dev.102(2–3),239–247 (1998).
    • 42  Tsukamoto H, Clise-Dwyer K, Huston GE et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc. Natl Acad. Sci. USA106(43),18333–18338 (2009).
    • 43  Jones SC, Clise-Dwyer K, Huston G et al. Impact of post-thymic cellular longevity on the development of age-associated CD4+ T cell defects. J. Immunol.180(7),4465–4475 (2008).
    • 44  Tsukamoto H, Huston GE, Dibble J, Duso DK, Swain SL. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol.185(8),4535–4544 (2010).• Identified reduced BIM expression as being responsible for prolonged survival of aged naive CD4 T cells.
    • 45  Gui J, Zhu X, Dohkan J, Cheng L, Barnes PF, Su DM. The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int. Immunol.19(10),1201–1211 (2007).
    • 46  Zhu X, Gui J, Dohkan J, Cheng L, Barnes PF, Su DM. Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell6(5),663–672 (2007).
    • 47  Sun L, Guo J, Brown R, Amagai T, Zhao Y, Su DM. Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell9(3),347–357 (2010).• Identified declining FoxN1 expression as a critical mediator of thymic epithelial cell degeneration.
    • 48  Sauce D, Larsen M, Fastenackels S et al. Evidence of premature immune aging in patients thymectomized during early childhood. J. Clin. Invest.119(10),3070–3078 (2009).• Demonstrates accelerated aging of the immune system in individuals thymectomized at an early age.
    • 49  Madhok AB, Chandrasekran A, Parnell V, Gandhi M, Chowdhury D, Pahwa S. Levels of recent thymic emigrant cells decrease in children undergoing partial thymectomy during cardiac surgery. Clin. Diagn. Lab. Immunol.12(5),563–565 (2005).
    • 50  Ogle BM, West LJ, Driscoll DJ et al. Effacing of the T cell compartment by cardiac transplantation in infancy. J. Immunol.176(3),1962–1967 (2006).
    • 51  Ahmed M, Lanzer KG, Yager EJ, Adams PS, Johnson LL, Blackman MA. Clonal expansions and loss of receptor diversity in the naive CD8 T cell repertoire of aged mice. J. Immunol.182(2),784–792 (2009).
    • 52  Czesnikiewicz-Guzik M, Lee WW, Cui D et al. T cell subset-specific susceptibility to aging. Clin. Immunol.127(1),107–118 (2008).
    • 53  Gupta S, Gollapudi S. TNF-α-induced apoptosis in human naive and memory CD8+ T cells in aged humans. Exp. Gerontol.41(1),69–77 (2006).
    • 54  Gupta S, Gollapudi S. CD95-mediated apoptosis in naive, central and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp. Gerontol.43(4),266–274 (2008).
    • 55  Smithey MJ, Renkema KR, Rudd BD, Nikolich-Zugich J. Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. Eur. J. Immunol.41(5),1352–1364 (2011).
    • 56  Cicin-Sain L, Smyk-Pearson S, Currier N et al. Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J. Immunol.184(12),6739–6745 (2010).
    • 57  Linton PJ, Li SP, Zhang Y, Bautista B, Huynh Q, Trinh T. Intrinsic versus environmental influences on T-cell responses in aging. Immunol. Rev.205,207–219 (2005).
    • 58  Cusi MG, Martorelli B, Di Genova G, Terrosi C, Campoccia G, Correale P. Age related changes in T cell mediated immune response and effector memory to respiratory syncytial virus (RSV) in healthy subjects. Immun. Ageing7,14 (2010).
    • 59  Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J. Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev.29(4),569–579 (2010).
    • 60  Hirokawa K, Utsuyama M, Ishikawa T et al. Decline of T cell-related immune functions in cancer patients and an attempt to restore them through infusion of activated autologous T cells. Mech. Ageing Dev.130(1–2),86–91 (2009).
    • 61  Rottinghaus EK, Vesosky B, Turner J. Interleukin-12 is sufficient to promote antigen-independent interferon-γ production by CD8 T cells in old mice. Immunology128(Suppl. 1),e679–e690 (2009).
    • 62  Ouyang X, Yang Z, Zhang R et al. Potentiation of Th17 cytokines in aging process contributes to the development of colitis. Cell Immunol.266(2),208–217 (2011).
    • 63  Wang L, Yi T, Zhang W, Pardoll DM, Yu H. IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res.70(24),10112–10120 (2010).
    • 64  Iida T, Iwahashi M, Katsuda M et al. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol. Rep.25(5),1271–1277 (2011).
    • 65  Wilke CM, Kryczek I, Wei S et al. Th17 cells in cancer: help or hindrance? Carcinogenesis32(5),643–649 (2011).
    • 66  Ahmad A, Banerjee S, Wang Z, Kong D, Majumdar AP, Sarkar FH. Aging and inflammation: etiological culprits of cancer. Curr. Aging Sci.2(3),174–186 (2009).
    • 67  Haynes L, Maue AC. Effects of aging on T cell function. Curr. Opin. Immunol.21(4),414–417 (2009).
    • 68  Maue AC, Yager EJ, Swain SL, Woodland DL, Blackman MA, Haynes L. T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol.30(7),301–305 (2009).
    • 69  Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J. Exp. Med.205(3),711–723 (2008).
    • 70  Parish ST, Wu JE, Effros RB. Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes. J. Clin. Immunol.30(6),798–805 (2010).
    • 71  Effros RB. Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. Exp. Gerontol.46(2–3),135–140 (2010).• Highlights recent findings in the T lymphocyte replicative senescence model, the role of latent viral infections and also addresses therapeutic approaches to retarding the process of senescence.
    • 72  Cortesini R, Lemaoult J, Ciubotariu R, Cortesini NS. CD8+CD28- T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol. Rev.182,201–206 (2001).
    • 73  Parish ST, Kim S, Sekhon RK, Wu JE, Kawakatsu Y, Effros RB. Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes. J. Immunol.184(6),2847–2854 (2010).
    • 74  Mackenzie WM, Hoskin DW, Blay J. Adenosine suppresses α(4)β(7) integrin-mediated adhesion of T lymphocytes to colon adenocarcinoma cells. Exp. Cell Res.276(1),90–100 (2002).
    • 75  Plunkett FJ, Franzese O, Finney HM et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J. Immunol.178(12),7710–7719 (2007).
    • 76  Meloni F, Morosini M, Solari N et al. Foxp3 expressing CD4+ CD25+ and CD8+CD28- T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum. Immunol.67(1–2),1–12 (2006).
    • 77  Tsukishiro T, Donnenberg AD, Whiteside TL. Rapid turnover of the CD8+CD28- T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol. Immunother.52(10),599–607 (2003).
    • 78  Chang WC, Li CH, Huang SC, Chang DY, Chou LY, Sheu BC. Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma. Cancer116(24),5777–5788 (2010).
    • 79  Urbaniak-Kujda D, Kapelko-Slowik K, Wolowiec D et al. Increased percentage of CD8+CD28- suppressor lymphocytes in peripheral blood and skin infiltrates correlates with advanced disease in patients with cutaneous T-cell lymphomas. Postepy. Hig. Med. Dosw. (Online)63,355–359 (2009).
    • 80  Kruger K, Buning C, Schriever F. Activated T lymphocytes bind in situ to stromal tissue of colon carcinoma but lack adhesion to tumor cells. Eur. J. Immunol.31(1),138–145 (2001).
    • 81  Becker JC, Vetter CS, Schrama D, Bröcker EB, thor Straten P. Differential expression of CD28 and CD94/NKG2 on T cells with identical TCR β variable regions in primary melanoma and sentinel lymph node. Eur. J. Immunol.30(12),3699–3706 (2000).
    • 82  Characiejus D, Pasukoniene V, Kazlauskaite N et al. Predictive value of CD8highCD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. Anticancer Res.22(6B),3679–3683 (2002).
    • 83  Characiejus D, Pasukoniene V, Jacobs JJ et al. Prognostic significance of peripheral blood CD8highCD57+ lymphocytes in bladder carcinoma patients after intravesical IL-2. Anticancer Res.31(2),699–703 (2011).
    • 84  Malaguarnera L, Cristaldi E, Malaguarnera M. The role of immunity in elderly cancer. Crit. Rev. Oncol. Hematol.74(1),40–60 (2010).
    • 85  Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor α blockers and malignancy in children: forty-eight cases reported to the food and drug administration. Arthritis Rheum.62(8),2517–2524 (2010).
    • 86  Zidi I, Mestiri S, Bartegi A, Amor NB. TNF-α and its inhibitors in cancer. Med. Oncol.27(2),185–198 (2009).
    • 87  Begley LA, Kasina S, MacDonald J, Macoska JA. The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy. Cytokine43(2),194–199 (2008).
    • 88  Barron DA, Strand DW, Ressler SJ et al. TGF-β1 induces an age-dependent inflammation of nerve ganglia and fibroplasia in the prostate gland stroma of a novel transgenic mouse. PLoS One5(10),e13751 (2010).
    • 89  Bianchi-Frias D, Vakar-Lopez F, Coleman IM, Plymate SR, Reed MJ, Nelson PS. The effects of aging on the molecular and cellular composition of the prostate microenvironment. PLoS One5(9),e12501 (2010).
    • 90  McDowell KL, Begley LA, Mor-Vaknin N, Markovitz DM, Macoska JA. Leukocytic promotion of prostate cellular proliferation. Prostate70(4),377–389 (2010).
    • 91  Anderson MJ, Shafer-Weaver K, Greenberg NM, Hurwitz AA. Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer. J. Immunol.178(3),1268–1276 (2007).
    • 92  Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (T ). PLoS One5(7),e11469 (2010).
    • 93  Fry TJ, Sinha M, Milliron M et al. Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood104(9),2794–2800 (2004).
    • 101  National Cancer Institute website. Surveillance, Epidemiology and End Results (SEER) database http://seer.cancer.gov/