Immunosenescence and Cancer Immunotherapy at Old Age: Basics

  • Tamas FulopEmail author
  • J. M. Witkowski
  • K. Hirokawa
  • A. Larbi
  • G. Pawelec
Living reference work entry


Age is the single most important risk factor for cancer development. Of the many age-associated changes paralleling increased cancer incidence, those of the immune system may play a major role in waning defense against tumorigenesis. Thus, immunosenescence may contribute to the higher rate of occurrence of tumors in the elderly. However, exactly how these age-related changes in immunity translate to cancer development is not well defined and understood. With the dramatic recent successes of immunotherapy in some patients for some tumors, there is an increasing concern that immunosenescence may temper responses in older patients. Nonetheless, existing anecdotal data suggest that success rates and side effects of first-generation checkpoint blockade immunotherapy in elderly patients are similar to those in younger subjects. However, success rates are still low, with only a fraction of patients obtaining clinical benefit in most trials, and it cannot yet be excluded that age may play a role in the failure of some therapies in some patients. Thus, although there are no reasons to refuse the elderly these treatments, appropriate clinical trials and not just anecdotal evidence are required to explore this issue further.


Immunosenescence Cancer Aging Inflamm-aging Immunotherapy Immune checkpoint inhibitors Adaptive immunity Innate immunity 



This work was partly supported by grants from the Canadian Institutes of Health Research (No. 106634 and No. 106701), the Université de Sherbrooke, and the Research Center on Aging, a grant from the Croeni Foundation (GP), Polish Ministry of Science and Higher Education statutory grant 02-0058/07/262 to JMW, and Agency for Science Technology and Research (A*STAR) to AL.


  1. Adeegbe DO1, Nishikawa H. Natural and induced T regulatory cells in cancer. Front Immunol. 2013;4:190.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Agrawal A, Agrawal S, Gupta S. Role of dendritic cells in inflammation and loss of tolerance in the elderly. Front Immunol. 2017;8:896.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Akbar AN, Henson SM. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol. 2011;11:289–95.PubMedCrossRefGoogle Scholar
  4. Albright JM, Dunn RC, Shults JA, Boe DM, Afshar M, Kovacs EJ. Advanced age alters monocyte and macrophage responses. Antioxid Redox Signal. 2016;25:805–15.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Аnisimov VN. Carcinogenesis and aging 20 years after: escaping horizon. Mech Ageing Dev. 2009;130:105–21.CrossRefGoogle Scholar
  6. Appay V, Sauce D. Naive T cells: the crux of cellular immune aging? Exp Gerontol. 2014;54:90–3.PubMedCrossRefGoogle Scholar
  7. Arlen PM. Neoantigens in the immuno-oncology space. Future Oncol. 2017;13:2209–11.PubMedCrossRefGoogle Scholar
  8. Azzaoui I, Uhel F, Rossille D, Pangault C, Dulong J, Le Priol J, Lamy T, Houot R, Le Gouill S, Cartron G, Godmer P, Bouabdallah K, Milpied N, Damaj G, Tarte K, Fest T, Roussel M. T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells. Blood. 2016;128:1081–92.PubMedCrossRefGoogle Scholar
  9. Bailur JK, Gueckel B, Derhovanessian E, Pawelec G. Presence of circulating Her2-reactive CD8 + T-cells is associated with lower frequencies of myeloid derived suppressor cells and regulatory T cells, and better survival in older breast cancer patients. Breast Cancer Res. 2015;17:34.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Baitsch L1, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. The three main stumbling blocks for anticancer T cells. Trends Immunol. 2012;33:364–72.PubMedCrossRefGoogle Scholar
  11. Bandaranayake T, Shaw AC. Host resistance and immune aging. Clin Geriatr Med. 2016;32:415–32.PubMedCrossRefGoogle Scholar
  12. Barnes TA, Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer. 2017;117:451–60.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bauer ME, de La Fuente M. The role of oxidative and inflammatory stress and persistent viral infections in immunosenescence. Mech Ageing Dev. 2016;158:27–37.PubMedCrossRefGoogle Scholar
  14. Beier UH, Wang L, Han R, Akimova T, Liu Y, Hancock WW. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci Signal. 2012;5:ra45.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bettonville M, D’Aria S, Braun MY. Metabolic programming in chronically stimulated T cells: lessons from cancer and viral infections. Eur J Immunol. 2016;46:1574–82.PubMedCrossRefGoogle Scholar
  16. Bonelli S, Geeraerts X, Bolli E, Keirsse J, Kiss M, Pombo Antunes AR, Van Damme H, De Vlaminck K, Movahedi K, Laoui D, Raes G, Van Ginderachter JA. Beyond the M-CSF receptor – novel therapeutic targets in tumor-associated macrophages. FEBS J. 2018;285(4):777–787.PubMedCrossRefGoogle Scholar
  17. Bryl E, Gazda M, Foerster J, Witkowski JM. Age-related increase of frequency of a new, phenotypically distinct subpopulation of human peripheral blood T cells expressing lowered levels of CD4. Blood. 2001;98:1100–7.PubMedCrossRefGoogle Scholar
  18. Capece D, Verzella D, Tessitore A, Alesse E, Capalbo C, Zazzeroni F. Cancer secretome and inflammation: the bright and the dark sides of NF-κB. Semin Cell Dev Biol. 2017. pii: S1084-9521(16)30485-2.Google Scholar
  19. Catakovic K, Klieser E, Neureiter D, Geisberger R. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 2017;15:1.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chang CI, Liao JC, Kuo L. Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res. 2001;61:1100–6.PubMedGoogle Scholar
  21. Channappanavar R, Twardy BS, Krishna P, Suvas S. Advancing age leads to predominance of inhibitory receptor expressing CD4 T cells. Mech Ageing Dev. 2009;130:709–12.PubMedCrossRefGoogle Scholar
  22. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–23.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Chen DS, Mellman I. Oncology meets immunology: the cancer immunity cycle. Immunity. 2013;39:1e10.Google Scholar
  24. Chidrawar S, Khan N, Wei W, McLarnon A, Smith N, Nayak L, Moss P. Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin Exp Immunol. 2009;155:423–32.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21:1424–35.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Coppé J-P, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell- nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.PubMedCrossRefGoogle Scholar
  27. Daste A, Domblides C, Gross-Goupil M, Chakiba C, Quivy A, Cochin V, de Mones E, Larmonier N, Soubeyran P, Ravaud A. Immune checkpoint inhibitors and elderly people: a review. Eur J Cancer. 2017;82:155–66.PubMedCrossRefGoogle Scholar
  28. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017;7:165–76.PubMedCrossRefGoogle Scholar
  29. Denkinger MD, Leins H, Schirmbeck R, Florian MC, Geiger H. HSC aging and senescent immune remodeling. Trends Immunol. 2015;36:815–24.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Douziech N, Seres I, Larbi A, Szikszay E, Roy PM, Arcand M, Dupuis G, Fulop T Jr. Modulation of human lymphocyte proliferative response with aging. Exp Gerontol. 2002;37:369–87.PubMedCrossRefGoogle Scholar
  31. Duan S, Thomas PG. Balancing immune protection and immune pathology by CD8(+) T-cell responses to influenza infection. Front Immunol. 2016;7:25.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.PubMedCrossRefGoogle Scholar
  33. Effros RB. Replicative senescence: the final stage of memory T cell differentiation? Curr HIV Res. 2003;1:153–65.PubMedCrossRefGoogle Scholar
  34. Eleftheriadis T, Pissas G, Antoniadi G, Spanoulis A, Liakopoulos V, Stefanidis I. Indoleamine 2,3-dioxygenase increases p53 levels in alloreactive human T cells, and both indoleamine 2,3-dioxygenase and p53 suppress glucose uptake, glycolysis and proliferation. Int Immunol. 2014;26:673–84.PubMedCrossRefGoogle Scholar
  35. Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: immune aging & checkpoint inhibitors. J Geriatr Oncol. 2017;8:229–35.PubMedCrossRefGoogle Scholar
  36. Fanoni D, Tavecchio S, Recalcati S, Balice Y, Venegoni L, Fiorani R, Crosti C, Berti E. New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas. Immunol Lett. 2011;134:157–60.PubMedCrossRefGoogle Scholar
  37. Ferguson SD, Srinivasan VM, Ghali MG, Heimberger AB. Cytomegalovirus-targeted immunotherapy and glioblastoma: hype or hope? Immunotherapy. 2016;8:413–23.PubMedCrossRefGoogle Scholar
  38. Flores RR, Clauson CL, Cho J, Lee BC, McGowan SJ, Baker DJ, Niedernhofer LJ, Robbins PD. Expansion of myeloid-derived suppressor cells with aging in the bone marrow of mice through a NF-κB-dependent mechanism. Aging Cell. 2017;16:480–7.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R, Ferlay J, editors. Cancer incidence in five continents, Vol. X (IARC scientific publication no. 164). Lyon: IARC; 2013.Google Scholar
  40. Fornara O, Odeberg J, Wolmer Solberg N, Tammik C, Skarman P, Peredo I, Stragliotto G, Rahbar A, Söderberg-Nauclér C. Poor survival in glioblastoma patients is associated with early signs of immunosenescence in the CD4 T-cell compartment after surgery. Oncoimmunology. 2015;4(9):e1036211.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Fougère B, Boulanger E, Nourhashémi F, Guyonnet S, Cesari M. Chronic inflammation: accelerator of biological aging. J Gerontol A Biol Sci Med Sci. 2017;72:1218–25.PubMedGoogle Scholar
  42. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.PubMedCrossRefGoogle Scholar
  43. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128:92–105.PubMedCrossRefGoogle Scholar
  44. Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D, Capri M. Immunobiography and the heterogeneity of immune responses in the elderly: a focus on Inflammaging and trained immunity. Front Immunol. 2017;8:982.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Frey AB. The inhibitory signaling receptor Protocadherin-18 regulates tumor-infiltrating CD8+ T-cell function. Cancer Immunol Res. 2017;5:920–8.PubMedCrossRefGoogle Scholar
  46. Fulop T, Larbi A, Douziech N, Fortin C, Guérard KP, Lesur O, Khalil A, Dupuis G. Signal transduction and functional changes in neutrophils with aging. Aging Cell. 2004;3:217–26.PubMedCrossRefGoogle Scholar
  47. Fulop T, Larbi A, Kotb R, de Angelis F, Pawelec G. Aging, immunity, and cancer. Discov Med. 2011;11:537–50.PubMedGoogle Scholar
  48. Fulop T, Larbi A, Kotb R, Pawelec G. Immunology of aging and cancer development. Interdiscip Top Gerontol. 2013a;38:38–48.PubMedCrossRefGoogle Scholar
  49. Fulop T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Front Immunol. 2013b;4:271.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Fulop T, Le Page A, Fortin C, Witkowski JM, Dupuis G, Larbi A. Cellular signaling in the aging immune system. Curr Opin Immunol. 2014;29:105–11.PubMedCrossRefGoogle Scholar
  51. Fulop T, Dupuis G, Baehl S, Le Page A, Bourgade K, Frost E, Witkowski JM, Pawelec G, Larbi A, Cunnane S. From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation. Biogerontology. 2016;17:147–57.PubMedCrossRefGoogle Scholar
  52. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, d’Adda di Fagagna F. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012;14:355–65.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer Immunol Res. 2017;5:3–8.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Galati D, Zanotta S. Hematologic neoplasms: dendritic cells vaccines in motion. Clin Immunol. 2017;183:181–90.PubMedCrossRefGoogle Scholar
  55. Geeraerts X, Bolli E, Fendt SM, Van Ginderachter JA. Macrophage metabolism as therapeutic target for Cancer, atherosclerosis, and obesity. Front Immunol. 2017;8:289.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Glienke W, Esser R, Priesner C, Suerth JD, Schambach A, Wels WS, Grez M, Kloess S, Arseniev L, Koehl U. Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol. 2015;6:21.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Gonzalez-Freire M, de Cabo R, Bernier M, Sollott SJ, Fabbri E, Navas P, Ferrucci L. Reconsidering the role of mitochondria in aging. J Gerontol A Biol Sci Med Sci. 2015;70:1334–42.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. Naïve T cell maintenance and function in human ageing. J Immunol. 2015;194:4073e80.CrossRefGoogle Scholar
  59. Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss PA. The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol. 2005;140:540–6.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144e56.CrossRefGoogle Scholar
  61. Guéry L, Hugues S. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int. 2015;2015:314620.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Guha P, Cunetta M, Somasundar P, Espat NJ, Junghans RP, Katz SC. Frontline science: functionally impaired geriatric CAR-T cells rescued by increased α5β1 integrin expression. J Leukoc Biol. 2017;102:201–8.PubMedCrossRefGoogle Scholar
  63. Haabeth OA, Lorvik KB, Hammarström C, Donaldson IM, Haraldsen G, Bogen B, Corthay A. Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nat Commun. 2011;2:240.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem. 2005;280:32081–9.PubMedCrossRefGoogle Scholar
  65. Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy. 2016;8:299–313.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.PubMedCrossRefGoogle Scholar
  67. Hazeldine J, Lord JM. Innate immunesenescence: underlying mechanisms and clinical relevance. Biogerontology. 2015;16:187–201.PubMedCrossRefGoogle Scholar
  68. Henson SM, Macaulay R, Riddell NE, Nunn CJ, Akbar AN. Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol. 2015;45:1441–51.PubMedCrossRefGoogle Scholar
  69. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti- PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Hirokawa K, Utsuyama M. Combined grafting of bone marrow and thymus, and sequential multiple thymus graftings in various strains of mice. The effect on immune functions and life span. Mech Ageing Dev. 1989;49:49e60.CrossRefGoogle Scholar
  71. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711e23.CrossRefGoogle Scholar
  72. Hoffmann M, Pantazis N, Martin GE, Hickling S, Hurst J, Meyerowitz J, Willberg CB, Robinson N, Brown H, Fisher M, Kinloch S, Babiker A, Weber J, Nwokolo N, Fox J, Fidler S, Phillips R, Frater J, SPARTAC and CHERUB Investigators. Exhaustion of activated CD8 T cells predicts disease progression in primary HIV-1 infection. PLoS Pathog. 2016;12:e1005661.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Huguet F, Tavitian S. Emerging biological therapies to treat acute lymphoblastic leukemia. Expert Opin Emerg Drugs. 2017;22:107–21.PubMedCrossRefGoogle Scholar
  74. Hurez V, Padrón ÁS, Svatek RS, Curiel TJ. Considerations for successful cancer immunotherapy in aged hosts. Clin Exp Immunol. 2017;187:53–63.PubMedCrossRefGoogle Scholar
  75. Hurt B, Schulick R, Edil B, El Kasmi KC, Barnett C Jr. Cancer-promoting mechanisms of tumor-associated neutrophils. Am J Surg. 2017;214:938. pii: S0002-9610(17)30604-9PubMedCrossRefGoogle Scholar
  76. 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;356:1795–9.PubMedCrossRefGoogle Scholar
  77. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33.PubMedCrossRefGoogle Scholar
  78. Jacqueline C, Bourfia C, Hbid H, Sorci G, Thomas F, Roche B. Interactions between immune challenges and cancer cells proliferation: timing does matter! Evol Med Publ Health. 2016;2016:299–311.CrossRefGoogle Scholar
  79. Jiang S1, Yan W. T-cell immunometabolism against cancer. Cancer Lett. 2016;382:255–8.PubMedCrossRefGoogle Scholar
  80. Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer. 2017;123:1904–11.PubMedCrossRefPubMedCentralGoogle Scholar
  81. Johnston-Carey HK, Pomatto LC, Davies KJ. The immunoproteasome in oxidative stress, aging, and disease. Crit Rev Biochem Mol Biol. 2015;51:268–81.PubMedCrossRefGoogle Scholar
  82. June CH, Maus MV, Plesa G, Johnson LA, Zhao Y, Levine BL, Grupp SA, Porter DL. Engineered T cells for cancer therapy. Cancer Immunol Immunother. 2014;63:969–75.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BW. The use of agonistic anti-CD40 therapy in treatments for cancer. Int Rev Immunol. 2012;31:246–66.PubMedCrossRefGoogle Scholar
  84. Kim HJ, Cantor H. CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res. 2014;2:91–8.PubMedCrossRefGoogle Scholar
  85. Kouidhi S, Elgaaied AB, Chouaib S. Impact of metabolism on T-cell differentiation and function and cross talk with tumor microenvironment. Front Immunol. 2017;13(8):270.Google Scholar
  86. Larbi A, Fulop T. From “truly naïve” to “exhausted senescent” T cells: when markers predict functionality. Cytometry A. 2014;85:25–35.PubMedCrossRefGoogle Scholar
  87. Larbi A, Dupuis G, Khalil A, Douziech N, Fortin C, Fülöp T Jr. Differential role of lipid rafts in the functions of CD4+ and CD8+ human T lymphocytes with aging. Cell Signal. 2006;18:1017–30.PubMedCrossRefGoogle Scholar
  88. Le Page A, Fortin C, Garneau H, Allard N, Tsvetkova K, Tan CT, Larbi A, Dupuis G, Fülöp T. Downregulation of inhibitory SRC homology 2 domain-containing phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly. Cell Commun Signal. 2014;12:2.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Li G, Yu M, Lee WW, Tsang M, Krishnan E, Weyand CM, Goronzy JJ. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med. 2012;18:1518–24.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Liu H, Yang H, Chen X, Lu Y, Zhang Z, Wang J, Zhang M, Xue L, Xue F, Liu G. Cellular metabolism modulation in T lymphocyte immunity. Immunology. 2014.Google Scholar
  91. Lowry LE, Zehring WA. Potentiation of natural killer cells for Cancer immunotherapy: a review of literature. Front Immunol. 2017;8:1061.PubMedPubMedCentralCrossRefGoogle Scholar
  92. MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31:259–83.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Manser AR, Uhrberg M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol Immunother. 2016;65:417e26.CrossRefGoogle Scholar
  94. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.PubMedCrossRefGoogle Scholar
  95. Margel D, Alkhateeb SS, Finelli A, Fleshner N. Diminished efficacy of bacille Calmette–Guerin among elderly patients with nonmuscle invasive bladder cancer. Urology. 2011;78:848–54.PubMedCrossRefGoogle Scholar
  96. Martínez-Lostao L, Anel A, Pardo J. How do cytotoxic lymphocytes kill cancer cells? Clin Cancer Res. 2015;21:5047–56.PubMedCrossRefGoogle Scholar
  97. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125:3356–64.PubMedPubMedCentralCrossRefGoogle Scholar
  98. McElhaney JE, Zhou X, Talbot HK, Soethout E, Bleackley RC, Granville DJ, Pawelec G. The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine. 2012;30:2060–7.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Melssen M, Slingluff CL Jr. Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol. 2017;47:85–92.PubMedCrossRefPubMedCentralGoogle Scholar
  100. Metcalf TU, Cubas RA, Ghneim K, Cartwright MJ, Grevenynghe JV, Richner JM, Olagnier DP, Wilkinson PA, Cameron MJ, Park BS, Hiscott JB, Diamond MS, Wertheimer AM, Nikolich-Zugich J, Haddad EK. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Ageing Cell. 2015;14:421e32.CrossRefGoogle Scholar
  101. Michalek RD, Rathmell JC. The metabolic life and times of a T-cell. Immunol Rev. 2010;236:190–202.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Mikulandra M, Pavelic J, Glavan TM. Recent findings on the application of toll-like receptors agonists in cancer therapy. Curr Med Chem. 2017;24:2011–32.PubMedCrossRefGoogle Scholar
  103. Mills CD, Harris RA, Ley K. Macrophage polarization: decisions that affect health. J Clin Cell Immunol. 2015;6(5):364.PubMedPubMedCentralGoogle Scholar
  104. Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, Morabito N, Lasco A, Gangemi S, Basile G. Inflammaging and anti-Inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp. 2016;64:111–26.CrossRefGoogle Scholar
  105. Molony RD, Malawista A, Montgomery RR. Reduced dynamic range of antiviral innate immune responses in aging. Exp Gerontol. 2017. pii: S0531-5565(17)30483-7.Google Scholar
  106. Moynihan KD, Irvine DJ. Roles for innate immunity in combination immunotherapies. Cancer Res. 2017;77:5215–21.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol. 2015;15:45–56.PubMedCrossRefGoogle Scholar
  108. Nguyen THO, Sant S, Bird NL, Grant EJ, Clemens EB, Koutsakos M, Valkenburg SA, Gras S, Lappas M, Jaworowski A, Crowe J, Loh L, Kedzierska K. Perturbed CD8+ T cell immunity across universal influenza epitopes in the elderly. J Leukoc Biol. 2018;103(2):321–339.Google Scholar
  109. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.PubMedGoogle Scholar
  110. Nyugen J, Agrawal S, Gollapudi S, Gupta S. Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol. 2010;30:806e13.CrossRefGoogle Scholar
  111. Ok CY, Young KH. Checkpoint inhibitors in hematological malignancies. J Hematol Oncol. 2017;10:103.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003;21:807–39.PubMedCrossRefGoogle Scholar
  113. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Park CB, Larsson NG. Mitochondrial DNA mutations in disease and aging. J Cell Biol. 2011;193:809–18.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9:15.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Pawelec G. Immunosenenescence: role of cytomegalovirus. Exp Gerontol. 2014;54:1–5.PubMedCrossRefGoogle Scholar
  117. Pawelec G. Immunosenescence and cancer. Biogerontology. 2017;18:717–21.PubMedCrossRefGoogle Scholar
  118. Pearce EL1, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009;460:103–7.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Pedicord VA, Cross JR, Montalvo-Ortiz W, Miller ML, Allison JP. Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD81 T cell priming to promote memory formation and metabolic readiness. J Immunol. 2015;194:2089–98.PubMedCrossRefGoogle Scholar
  120. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science. 2016;354:481–4.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Pera A, Campos C, Lopez N, Hassouneh F, Alonso C, Tarazona R, Solana R. Immunosenescence: implications for response to infection and vaccination in older people. Maturitas. 2015;82:50e5.CrossRefGoogle Scholar
  122. Petrova G, Ferrante A, Gorski J. Cross-reactivity of T cells and its role in the immune system. Crit Rev Immunol. 2012;32:349–72.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Phillips AC, Carroll D, Drayson MT, Der G. Salivary immunoglobulin a secretion rate is negatively associated with cancer mortality: the west of Scotland twenty-07 study. PLoS One. 2015;10(12):e0145083.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Rao SG, Jackson JG. SASP: tumor suppressor or promoter? Yes! Trends Cancer. 2016;2:676–87.PubMedCrossRefGoogle Scholar
  126. Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA. Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol. 2012;24:482–7.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.PubMedCrossRefGoogle Scholar
  128. Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response. 2014;12:288–341.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol. 2013;43:889–96.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Roth GS, Ingram DK. Manipulation of health span and function by dietary caloric restriction mimetics. Ann N Y Acad Sci. 2016;1363:5–10.PubMedCrossRefGoogle Scholar
  131. Ruggeri L, Mancusi A, Burchielli E, Capanni M, Carotti A, Aloisi T, Aversa F, Martelli MF, Velardi A. NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation. Blood Cells Mol Dis. 2008;40:84–90.PubMedCrossRefGoogle Scholar
  132. Saavedra D, Garcia B, Lage A. T cell subpopulations in healthy elderly and lung Cancer patients: insights from Cuban studies. Front Immunol. 2017;8:146.PubMedPubMedCentralGoogle Scholar
  133. Satoh T, Akira S. Toll-like receptor signaling and its inducible proteins. Microbiol Spectr. 2016;4(6).Google Scholar
  134. Schamel WW, Alarcon B, Höfer T, Minguet S. The Allostery model of TCR regulation. J Immunol. 2017;198:47–52.PubMedCrossRefGoogle Scholar
  135. Setrerrahmane S, Xu H. Tumor-related interleukins: old validated targets for new anti-cancer drug development. Mol Cancer. 2017;16:153.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Sgambato A, Casaluce F, Gridelli C. The role of checkpoint inhibitors immunotherapy in advanced non-small cell lung cancer in the elderly. Expert Opin Biol Ther. 2017;17:565–71.PubMedCrossRefGoogle Scholar
  137. Shapiro M, Nandi B, Pai 1C, Samur MK, Pelluru D, Fulciniti M, Prabhala RH RH, Munshi NC, Gold JS. Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis. Cancer Immunol Immunother. 2016;65:13–24.PubMedCrossRefGoogle Scholar
  138. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.PubMedCrossRefGoogle Scholar
  139. Shipp C, Speigl L, Janssen N, Martens A, Pawelec G. A clinical and biological perspective of human myeloid-derived suppressor cells in cancer. Cell Mol Life Sci. 2016;73:4043–61.PubMedCrossRefGoogle Scholar
  140. Sica A, Strauss L. Energy metabolism drives myeloid-derived suppressor cell differentiation and functions in pathology. J Leukoc Biol. 2017;102(2):325–334.PubMedCrossRefGoogle Scholar
  141. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012;24:331–41.PubMedCrossRefGoogle Scholar
  142. Sun HL, Zhou X, Xue YF, Wang K, Shen YF, Mao JJ, Guo HF, Miao ZN. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol. 2012;18:3303–9.PubMedPubMedCentralGoogle Scholar
  143. Tang YC, Thoman M, Linton PJ, Deisseroth A. Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged. Cancer Immunol Immunother. 2009;58:1949–57.PubMedCrossRefGoogle Scholar
  144. Tarazona R, Campos C, Pera A, Sanchez-Correa B, Solana R. Flow cytometry analysis of NK cell phenotype and function in aging. Methods Mol Biol. 2015;1343:9–18.PubMedCrossRefGoogle Scholar
  145. Tarazona R, Sanchez-Correa B, Casas-Avilés I, Campos C, Pera A, Morgado S, López-Sejas N, Hassouneh F, Bergua JM, Arcos MJ, Bañas H, Casado JG, Durán E, Labella F, Solana R. Immunosenescence: limitations of natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2017;66:233–45.PubMedCrossRefGoogle Scholar
  146. Topalian SL. Targeting immune checkpoints in cancer therapy. JAMA. 2017;318(17):1647–1648.PubMedCrossRefGoogle Scholar
  147. Turner JE, Brum PC. Does regular exercise counter T cell Immunosenescence reducing the risk of developing Cancer and promoting successful treatment of malignancies? Oxidative Med Cell Longev. 2017;2017:4234765.Google Scholar
  148. Vacca P, Montaldo E, Croxatto D, Moretta F, Bertaina A, Vitale C, Locatelli F, Mingari MC, Moretta L. NK cells and other innate lymphoid cells in hematopoietic stem cell transplantation. Front Immunol. 2016;7:188.PubMedPubMedCentralCrossRefGoogle Scholar
  149. van der Geest KS, Abdulahad WH, Tete SM, Lorencetti PG, Horst G, Bos NA, Kroesen BJ, Brouwer E, Boots AM. Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp Gerontol. 2014;60:190–6.PubMedCrossRefGoogle Scholar
  150. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36:68–78.PubMedCrossRefGoogle Scholar
  151. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ, Ahmed R, Amara RR. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458:206–10.PubMedCrossRefGoogle Scholar
  152. Verschoor CP, Johnstone J, Millar J, Dorrington MG, Habibagahi M, Lelic A, Loeb M, Bramson JL, Bowdish DM. Blood CD33(þ)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol. 2013;93:633e7.CrossRefGoogle Scholar
  153. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–71.PubMedCrossRefGoogle Scholar
  154. Vina J, Borras C, Abdelaziz KM, Garcia-Valles R, Gomez-Cabrera MC. The free radical theory of aging revisited: the cell signaling disruption theory of aging. Antioxid Redox Signal. 2013;19:779–87.PubMedPubMedCentralCrossRefGoogle Scholar
  155. Wang X, Huang S, Zhang Y, Zhu L, Wu X. The application and mechanism of PD pathway blockade for cancer therapy. Postgrad Med J. 2018;94(1107):53–60.PubMedCrossRefGoogle Scholar
  156. Watkins SK, Egilmez NK, Suttles J, Stout RD. IL-12 rapidly alters the functional profile of tumor-associated and tumor infiltrating macrophages in vitro and in vivo. J Immunol. 2007;178:1357–62.PubMedCrossRefGoogle Scholar
  157. Weyand CM, Goronzy JJ. Aging of the immune system. Mechanisms and therapeutic targets. Ann Am Thorac Soc. 2016;13(Suppl 5):S422–8.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004;78:5535–45.PubMedPubMedCentralCrossRefGoogle Scholar
  159. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99.PubMedPubMedCentralCrossRefGoogle Scholar
  160. Xu W, Larbi A. Markers of T cell senescence in humans. Int J Mol Sci. 2017;10(8):18.Google Scholar
  161. Yanes RE, Gustafson CE, Weyand CM, Goronzy JJ. Lymphocyte generation and population homeostasis throughout life. Semin Hematol. 2017;54:33e8.CrossRefGoogle Scholar
  162. Yang Y, Li T, Nielsen ME. Aging and cancer mortality: dynamics of change and sex differences. Exp Gerontol. 2012;47:695–705.PubMedPubMedCentralCrossRefGoogle Scholar
  163. Zarour HM. Reversing T-cell dysfunction and exhaustion in Cancer. Clin Cancer Res. 2016;22:1856–64.PubMedPubMedCentralCrossRefGoogle Scholar
  164. Zhang X, Meng X, Chen Y, Leng SX, Zhang H. The biology of aging and cancer. Cancer J. 2017;23:201–5.PubMedGoogle Scholar
  165. Zhao Y, Wu T, Shao S, Shi B, Zhao Y. Phenotype, development, and biological function of myeloid-derived suppressor cells. Oncoimmunology. 2015;5:e1004983.PubMedPubMedCentralCrossRefGoogle Scholar
  166. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445–89.PubMedPubMedCentralCrossRefGoogle Scholar
  167. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv324.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Tamas Fulop
    • 1
    Email author
  • J. M. Witkowski
    • 2
  • K. Hirokawa
    • 3
  • A. Larbi
    • 4
  • G. Pawelec
    • 5
    • 6
  1. 1.Research Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health SciencesUniversity of SherbrookeSherbrookeCanada
  2. 2.Department of PathophysiologyMedical University of GdańskGdańskPoland
  3. 3.Department of Pathology, Nitobe Memorial Nakano General HospitalInstitute for Health and Life SciencesTokyoJapan
  4. 4.Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A-Star)SingaporeSingapore
  5. 5.Department of Internal Medicine II, Center for Medical ResearchUniversity of TübingenTübingenGermany
  6. 6.Health Sciences North Research InstituteSudburyCanada

Section editors and affiliations

  • T. Fulop
    • 1
  1. 1.Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of MedicineUniversity of SherbrookeSherbrookeCanada

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