Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 10/2004

01-10-2004 | Review

Replicative senescence of CD8 T cells: potential effects on cancer immune surveillance and immunotherapy

Author: Rita B. Effros

Published in: Cancer Immunology, Immunotherapy | Issue 10/2004

Login to get access

Abstract

The process of replicative senescence, which stringently limits the proliferative potential of normal T cells, constitutes a potential problem for cancer immunotherapy. The ability of CD8 T cells to recognize and destroy tumor cells has been well-established, but the requirement for massive, prolonged proliferative T-cell expansion and maintenance of functional integrity poses a significant obstacle to the success of cancer immunotherapy. Cancer immune surveillance may also be compromised by the long-term exposure of T cells to tumor antigens, particularly those of latent viruses, which could drive certain T cells to replicative senescence. This review summarizes the major characteristics of T-cell replicative senescence and raises the possibility that this process has the potential to affect both cancer development and treatment. Experimental strategies aimed at preventing T-cell replicative senescence are discussed in the context of cancer immunotherapy and vaccines.
Literature
1.
Alexandroff AB, McIntyre CA, Porter JC, Zeuthen J, Vile RG, Taub DD (1998) Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer. Br J Cancer 77:1806PubMed
2.
Appay V, Rowland-Jones S (2002) Premature ageing of the immune system: the cause of AIDS? Trends Immunol 23:580
3.
Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8:379CrossRefPubMed
4.
Azuma M, Phillips JH, Lanier LL (1993) CD28- T lymphocytes: antigenic and functional properties. J Immunol 150:1147PubMed
5.
Ballen K, Stewart FM (1997) Adoptive immunotherapy. Curr Opin Oncol 9:579PubMed
6.
Beverly B, Kang S, Lenardo M, Schwartz R (1992) Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol 4:661PubMed
7.
Bodnar AG, Kim NW, Effros RB, Chiu CP (1996) Mechanism of telomerase induction during T cell activation. Exp Cell Res 228:58CrossRefPubMed
8.
Boucher N, Defeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schachter F (1998) CD28 expression in T cell aging and human longevity. Exp Gerontol 33:267CrossRefPubMed
9.
Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA (2003) Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101:2711CrossRefPubMed
10.
Brenner MK, Heslop HE, Rooney CM (1998) Gene and cell transfer for specific immunotherapy. Vox Sang 74[Suppl 2]:87
11.
Brocker T, Karjalainen K (1998) Adoptive tumor immunity mediated by lymphocytes bearing modified antigen-specific receptors. Adv Immunol 68:257PubMed
12.
13.
Campisi J (2001) From cells to organisms: can we learn about aging from cells in culture? Exp Gerontol 36:607CrossRefPubMed
14.
15.
Carlens S, Liu D, Ringden O, Aschan J, Christensson B, Levitsky V, Dilber MS (2002) Cytolytic T cell reactivity to Epstein-Barr virus is lost during in vitro T cell expansion. J Hematother Stem Cell Res 11:669CrossRefPubMed
16.
Chakraborty NG, Stevens RL, Mehrotra S, Laska E, Taxel P, Sporn JR, Schauer P, Albertsen PC (2003) Recognition of PSA-derived peptide antigens by T cells from prostate cancer patients without any prior stimulation. Cancer Immunol Immunother 52:497CrossRefPubMed
17.
Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410:106CrossRefPubMed
18.
Characiejus D, Pasukoniene V, Kazlauskaite N, Valuckas KP, Petraitis T, Mauricas M, Den Otter W (2002) Predictive value of CD8highCD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. Anticancer Res 22:3679PubMed
19.
Cheever MA, Chen W (1997) Therapy with cultured T cells: principles revisited. Immunol Rev 157:177PubMed
20.
Chiu CP, Harley CB (1997) Replicative senescence and cell immortality: the role of telomeres and telomerase. Proc Soc Exp Biol Med 214:99–106PubMed
21.
Chua D, Huang J, Zheng B, Lau SY, Luk W, Kwong DL, Sham JS, Moss D, Yuen KY, Im SW, Ng MH (2001) Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 94:73CrossRefPubMed
22.
Cortesini R, LeMaoult J, Ciubotariu R, Cortesini NS (2001) CD8+CD28- T suppressor cells and the induction of antigen-specific antigen-presenting cells-mediated suppression of Th reactivity. Immunol Rev 182:201CrossRefPubMed
23.
Cristofalo V (1985) The destiny of cells: mechanisms and implications of senescence. Gerontologist 25:577PubMed
24.
Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT (1995) Estrogens, the immune response, and autoimmunity. Clin Exp Rheumatol 13:217PubMed
25.
Dagarag MD, Effros RB (2003) Ectopic telomerase expression prevents functional and phenotypic alterations associated with replicative senescence in virus-specific CD8 T cells. Clin Immunol (FOCIS Meeting Abstract Book)
26.
Dagarag MD, Ng H, Lubong R, Effros RB, Yang OO (2003) Differential impairment of lytic and cytokine functions in senescent HIV-1-specific cytotoxic T lymphocytes. J Virol 77:3077CrossRefPubMed
27.
Effros RB (1998) Replicative senescence in the immune system: impact of the Hayflick limit on T-cell function in the elderly. Am J Hum Genet 62:1003CrossRefPubMed
28.
Effros RB, Pawelec G (1997) Replicative senescence of T lymphocytes: does the Hayflick limit lead to immune exhaustion? Immunol Today 18:450–454CrossRefPubMed
29.
Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schachter F (1994) Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 29:601CrossRefPubMed
30.
Effros RB, Zhu X, Walford RL (1994) Stress response of senescent T lymphocytes: reduced hsp70 is independent of the proliferative block. J Gerontol 49:B65PubMed
31.
Effros RB, Allsopp R, Chiu CP, Wang L, Hirji K, Harley CB, Villeponteau B, West M, Giorgi JV (1996) Shortened telomeres in the expanded CD28-CD8+ subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS/Fast Track 10:F17
32.
Effros RB, Cai Z, Linton PJ (2003) CD8 T cells and aging. Crit Rev Immunol 23:45PubMed
33.
Fernandez N, Duffour MT, Perricaudet M, Lotze MT, Tursz T, Zitvogel L (1998) Active specific T-cell-based immunotherapy for cancer: nucleic acids, peptides, whole native proteins, recombinant viruses, with dendritic cell adjuvants or whole tumor cell-based vaccines: principles and future prospects. Cytokines Cell Mol Ther 4:53PubMed
34.
Foss FM (2002) Immunologic mechanisms of antitumor activity. Semin Oncol 29:5CrossRef
35.
Fox HS, Bond BL, Parslow TG (1991) Estrogen regulates the IFN-gamma promoter. J Immunol 146:4362PubMed
36.
Freitas AA, Rocha B (2000) Population biology of lymphocytes: the flight for survival. Annu Rev Immunol 18:83CrossRefPubMed
37.
Gitlitz BJ, Belldegrun AS, Figlin RA (2001) Vaccine and gene therapy of renal cell carcinoma. Semin Urol Oncol 19:141PubMed
38.
Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O’Fallon WM, Weyand CM (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75:12182CrossRefPubMed
39.
Grimm EA, Bruner JM, Carinhas J, Keoppen JA, Loudon WG, Owen-Schaub L, Steck PA, Moser RP (1990) Characterization of interleukin-2-initiated versus OKT3-initiated human tumor-infiltrating lymphocytes from glioblastoma multiforme: growth characteristics, cytolytic activity, and cell phenotype. Cancer Immunol Immunother 32:391
40.
Hakansson A, Hakansson L, Gustafsson B, Krysander L, Rettrup B, Ruiter D, Bernsen MR (2002) Biochemotherapy of metastatic malignant melanoma: on down-regulation of CD28. Cancer Immunol Immunother 51:499CrossRefPubMed
41.
Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, Van Lier RA (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 186:1407CrossRefPubMed
42.
Hathcock KS, Weng NP, Merica R, Jenkins MK, Hodes R (1998) Antigen-dependent regulation of telomerase activity in murine T cells. J Immunol 160:5702PubMed
43.
Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M (1995) Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155:3711PubMed
44.
Hooijberg E, Ruizendaal JJ, Snijders PJ, Kueter EW, Walboomers JM, Spits H (2000) Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase. J Immunol 165:4239PubMed
45.
Israel BF, Kenney SC (2003) Virally targeted therapies for EBV-associated malignancies. Oncogene 22:5122CrossRefPubMed
46.
Kennedy-Smith AG, McKenzie JL, Owen MC, Davidson PJ, Vuckovic S, Hart DN (2002) Prostate specific antigen inhibits immune responses in vitro: a potential role in prostate cancer. J Urol 168:741CrossRefPubMed
47.
Kitchingman GR, Rooney C (1998) Cytotoxic T cells and immunotherapy [comment]. Pediatr Radiol 28:489CrossRefPubMed
48.
Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 98:12072CrossRefPubMed
49.
Kyo S, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, Orimo A, Inoue M (1999) Estrogen activates telomerase. Cancer Res 59:5917–5921PubMed
50.
Lanier LL (2001) A renaissance for the tumor immunosurveillance hypothesis. Nat Med 7:1178PubMed
51.
Looney RJ, Falsey A, Campbell D, Torres A, Kolassa J, Brower C, McCann R, Menegus M, McCormick K, Frampton M, Hall W, Abraham GN (1999) Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol 90:213CrossRefPubMed
52.
Maini MK, Soares MV, Zilch CF, Akbar AN, Beverley PC (1999) Virus-induced CD8+ T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence. J Immunol 162:4521PubMed
53.
Migliaccio M, Amacker M, Just T, Reichenbach P, Valmori D, Cerottini JC, Romero P, Nabholz M (2000) Ectopic human telomerase catalytic subunit expression maintains telomere length but is not sufficient for CD8+ T lymphocyte immortalization. J Immunol 165:4978PubMed
54.
Mitchell MS (2002) Cancer vaccines, a critical review--part I. Curr Opin Investig Drugs 3:140PubMed
55.
Mollet L, Sadat-Sowti B, Duntze J, Leblond V, Bergeron F, Calvez V, Katlama C, Debrae P, Autran B (1998) CD8hi+CD57+ T lymphocytes are enriched in antigen-specific T cells capable of down-modulating cytotoxic activity. Int Immunol 10:311CrossRefPubMed
56.
Monteiro J, Batliwalla F, Ostrer H, Gregersen PK (1996) Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol 156:3587PubMed
57.
Mori A, Takao S, Pradutkanchana J, Kietthubthew S, Mitarnun W, Ishida T (2003) High tumor necrosis factor-alpha levels in the patients with Epstein-Barr virus-associated peripheral T-cell proliferative disease/lymphoma. Leuk Res 27:493CrossRefPubMed
58.
O’Reilly RJ, Small TN, Papadopoulos E, Lucas K, Lacerda J, Koulova L (1998) Adoptive immunotherapy for Epstein-Barr virus-associated lymphoproliferative disorders complicating marrow allografts. Springer Semin Immunopathol 20:455CrossRefPubMed
59.
60.
Pawelec G (2003) Editorial statement from Graham Pawelec. Cancer Immunol Immunother 52
61.
Pawelec G, Schneider EM, Wernet P (1986) Acquisition of suppressive activity and natural killer-like cytotoxicity by human alloproliferative “helper” T cell clones. J Immunol 136:402PubMed
62.
Perillo NL, Naeim F, Walford RL, Effros RB (1993) The in vitro senescence of human lymphocytes: failure to divide is not associated with a loss of cytolytic activity or memory T cell phenotype. Mech Ageing Dev 67:173CrossRefPubMed
63.
Petersen JL, Morris CR, Solheim JC (2003) Virus evasion of MHC class I molecule presentation. J Immunol 171:4473PubMed
64.
Pittet MJ, Zippelius A, Speiser DE, Assenmacher M, Guillaume P, Valmori D, Lienard D, Lejeune F, Cerottini JC, Romero P (2001) Ex vivo IFN-gamma secretion by circulating CD8 T lymphocytes: implications of a novel approach for T cell monitoring in infectious and malignant diseases. J Immunol 166:7634PubMed
65.
Porter V (1994) Cellular senescence of T lymphocytes in vitro: a model system for the study of the age associated decline in immune functioning. Dissertation, UCLA Medical School
66.
Posnett DN, Sinha R, Kabak S, Russo C (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammopathy”. J Exp Med 179:609PubMed
67.
Posnett DN, Edinger JW, Manavalan JS, Irwin C, Marodon G (1999) Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones. Int Immunol 11:229CrossRefPubMed
68.
Salas AP, Chang AE (1998) Genetic approaches to adoptive cellular immunotherapy. Surg Oncol Clin N Am 7:487PubMed
69.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708CrossRefPubMed
70.
Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B (2002) Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168:5893PubMed
71.
Schirmer M, Goldberger C, Wurzner R, Duftner C, Pfeiffer KP, Clausen J, Neumayr G, Falkenbach A (2002) Circulating cytotoxic CD8(+) CD28(-) T cells in ankylosing spondylitis. Arthritis Res 4:71CrossRefPubMed
72.
Schwab R, Szabo P, Manavalan JS, Weksler ME, Posnett DN, Pannetier C, Kourilsky P, Even J (1997) Expanded CD4+ and CD8+ T cell clones in elderly humans. J Immunol 158:4493PubMed
73.
Shay J, Wright W (1996) Telomerase activity in human cancer. Curr Opin Oncol 8:66PubMed
74.
Shimizu Y, Van Seventer G, Ennis E, Newman W, Horgan K, Shaw S (1992) Crosslinking of the T cell-specific accessory moleculesCD7 and CD28 modulates T cell adhesion. J Exp Med 175:577PubMed
75.
Smith JR and Pereira-Smith OM (1996) Replicative senescence: implications for in vivo aging and tumor suppression. Science 273:63PubMed
76.
Spaulding CS, Guo W, Effros RB (1999) Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 34:633CrossRefPubMed
77.
Straathof KC, Bollard CM, Rooney CM, Heslop HE (2003) Immunotherapy for Epstein-Barr virus-associated cancers in children. Oncologist 8:83PubMed
78.
Sze DM, Giesajtis G, Brown RD, Raitakari M, Gibson J, Ho J, Baxter AG, Fazekas de St GB, Basten A, Joshua DE (2001) Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8(+)CD57(+)CD28(-) compartment. Blood 98:2817CrossRefPubMed
79.
Topp MS, Riddell SR, Akatsuka Y, Jensen MC, Blattman JN, Greenberg PD (2003) Restoration of CD28 expression in CD28- CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production. J Exp Med 198:947CrossRefPubMed
80.
Townsend SE, Allison JP (1993) Tumor rejection after direct costimulation of CD28+ T cells by B7-transfected melanoma cells. Science 259:368PubMed
81.
Tsai V, Kawashima I, Keogh E, Daly K, Sette A, Celis E (1998) In vitro immunization and expansion of antigen-specific cytotoxic T lymphocytes for adoptive immunotherapy using peptide-pulsed dendritic cells. Crit Rev Immunol 18:65PubMed
82.
Tsukishiro T, Donnenberg AD, Whiteside TL (2003) 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 52:599CrossRefPubMed
83.
Valenzuela HF, Effros RB (2002) Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol 105:117CrossRefPubMed
84.
Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley C (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661
85.
Wang RF, Rosenberg SA (1996) Human tumor antigens recognized by T lymphocytes: implications for cancer therapy. J Leukoc Biol 60:296PubMed
86.
Wang E, Lee MJ, Pandey S (1994) Control of fibroblast senescence and activation of programmed cell death. J Cell Biochem 54:432PubMed
87.
Weng NP, Levine BL, June CH, Hodes RJ (1995) Human naive and memory T lymphocytes differ in telomere length and replicative potential. Proc Natl Acad Sci U S A 92:11091PubMed
88.
Weng NP, Levine BL, June CH, Hodes RJ (1996) Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183:2471PubMed
89.
Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F (2002) Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol 37:445CrossRefPubMed
90.
Wills MR, Okecha G, Weekes MP, Gandhi MK, Sissons PJ, Carmichael AJ (2002) Identification of naive or antigen-experienced human CD8(+) T cells by expression of costimulation and chemokine receptors: analysis of the human cytomegalovirus-specific CD8(+) T cell response. J Immunol 168:5455PubMed
91.
Xu D, Erickson S, Szeps M, Gruber A, Sangfelt O, Einhorn S, Pisa P, Grander D (2000) Interferon alpha down-regulates telomerase reverse transcriptase and telomerase activity in human malignant and nonmalignant hematopoietic cells. Blood 96:4313PubMed
92.
Yee C, Riddell SR, Greenberg PD (1997) Prospects for adoptive T cell therapy. Curr Opin Immunol 9:702CrossRefPubMed
93.
Zanussi S, Vaccher E, Caffau C, Pratesi C, Crepaldi C, Bortolin MT, Tedeschi R, Politi D, Barzan L, Tirelli U, De Paoli P (2003) Interferon-gamma secretion and perforin expression are impaired in CD8+ T lymphocytes from patients with undifferentiated carcinoma of nasopharyngeal type. Cancer Immunol Immunother 52:28PubMed
94.
Zhang D, Shankar P, Xu Z, Harnisch B, Chen G, Lange C, Lee SJ, Valdez H, Lederman MM, Lieberman J (2003) Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 101:226CrossRefPubMed
Metadata
Title
Replicative senescence of CD8 T cells: potential effects on cancer immune surveillance and immunotherapy
Author
Rita B. Effros
Publication date
01-10-2004
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 10/2004
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-004-0508-x

Other articles of this Issue 10/2004

Cancer Immunology, Immunotherapy 10/2004 Go to the issue

Review

Effective immunotherapy against cancer

Review

Down-regulation of ζ-chain expression in T cells: a biomarker of prognosis in cancer?

Review

The paradox of T cell–mediated antitumor immunity in spite of poor clinical outcome in human melanoma

Review

Escape from immunotherapy: possible mechanisms that influence tumor regression/progression

Review

The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape

Editorial

Tumour escape from the immune response
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits