Seminars in Immunopathology

, Volume 41, Issue 1, pp 125–131 | Cite as

Does patient age influence anti-cancer immunity?

  • Graham PawelecEmail author


Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient’s own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti-cancer immunity may be compromised in the elderly due to (i) their low amounts of naïve T cells (potentially leading to holes in the repertoire for neoantigens), (ii) “exhaustion” of potentially tumor-specific memory T cells, and (iii) higher amounts of suppressive cells. Encouragingly, but only anecdotally, accumulated clinical experience suggests that advanced age does not result in poorer responses or greater toxicity in elderly patients treated with anti-CTLA-4 or anti-PD-1/PD-L1 antibodies. Here, I briefly contrast immune features of the elderly with the young, commonly referred to as “immunosenescence,” and the influence of patient age on the outcome of checkpoint blockade. As newer agents are licensed, and new combinations tested, broader and more detailed studies focusing on the age question will be crucial and should be taken into consideration when designing clinical trials.


Checkpoint blockade Immunosenescence Melanoma Anti-CTLA-4 Anti-PD-1/PD-L1 Geriatric oncology 


  1. 1.
    Pawelec G (2018) Age and immunity: what is "immunosenescence"? Exp Gerontol 105:4–9CrossRefGoogle Scholar
  2. 2.
    Daste A, Domblides C, Gross-Goupil M, Chakiba C, Quivy A, Cochin V, de Mones E, Larmonier N, Soubeyran P, Ravaud A (2017) Immune checkpoint inhibitors and elderly people: a review. Eur J Cancer 82:155–166CrossRefGoogle Scholar
  3. 3.
    Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG (1998) Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev 102:187–198CrossRefGoogle Scholar
  4. 4.
    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 37:445–453CrossRefGoogle Scholar
  5. 5.
    Hurez V, Padron A, Svatek RS, Curiel TJ (2018) Considerations for successful cancer immunotherapy in aged hosts. Exp Gerontol 107:27–36CrossRefGoogle Scholar
  6. 6.
    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488–2498CrossRefGoogle Scholar
  7. 7.
    Leins H, Mulaw M, Eiwen K, Sakk V, Liang Y, Denkinger M, Geiger H, Schirmbeck R (2018) Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood.
  8. 8.
    Kerber RA, O'Brien E, Cawthon RM (2009) Gene expression profiles associated with aging and mortality in humans. Aging Cell 8:239–250CrossRefGoogle Scholar
  9. 9.
    Florian MC, Klenk J, Marka G, Soller K, Kiryakos H, Peter R, Herbolsheimer F, Rothenbacher D, Denkinger M, Geiger H (2017) Expression and activity of the small RhoGTPase Cdc42 in blood cells of older adults are associated with age and cardiovascular disease. J Gerontol A Biol Sci Med Sci 72:1196–1200CrossRefGoogle Scholar
  10. 10.
    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 (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105CrossRefGoogle Scholar
  11. 11.
    Fulop T, Witkowski JM, Pawelec G, Alan C, Larbi A (2014) On the immunological theory of aging. Interdiscip Top Gerontol 39:163–176CrossRefGoogle Scholar
  12. 12.
    Verschoor CP, Johnstone J, Millar J, Dorrington MG, Habibagahi M, Lelic A, Loeb M, Bramson JL, Bowdish DM (2013) Blood CD33(+)HLA-DR(−) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol 93:633–637CrossRefGoogle Scholar
  13. 13.
    Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24:491–494CrossRefGoogle Scholar
  14. 14.
    Della Bella S, Bierti L, Presicce P, Arienti R, Valenti M, Saresella M, Vergani C, Villa ML (2007) Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol 122:220–228CrossRefGoogle Scholar
  15. 15.
    Blomberg BB, Frasca D (2013) Age effects on mouse and human B cells. Immunol Res 57:354–360CrossRefGoogle Scholar
  16. 16.
    Bulati M, Caruso C, Colonna-Romano G (2017) From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”. Ageing Res Rev 36:125–136CrossRefGoogle Scholar
  17. 17.
    Henson SM, Riddell NE, Akbar AN (2012) Properties of end-stage human T cells defined by CD45RA re-expression. Curr Opin Immunol 24:476–481CrossRefGoogle Scholar
  18. 18.
    Larbi A, Pawelec G, Wong SC, Goldeck D, Tai JJ, Fulop T (2011) Impact of age on T cell signaling: a general defect or specific alterations? Ageing Res Rev 10:370–378CrossRefGoogle Scholar
  19. 19.
    Holland AM, van den Brink MR (2009) Rejuvenation of the aging T cell compartment. Curr Opin Immunol 21:454–459CrossRefGoogle Scholar
  20. 20.
    Jagger A, Shimojima Y, Goronzy JJ, Weyand CM (2014) Regulatory T cells and the immune aging process: a mini-review. Gerontology 60:130–137CrossRefGoogle Scholar
  21. 21.
    Su DM, Aw D, Palmer DB (2013) Immunosenescence: a product of the environment? Curr Opin Immunol 25:498–503CrossRefGoogle Scholar
  22. 22.
    Oh J, Lee YD, Wagers AJ (2014) Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 20:870–880CrossRefGoogle Scholar
  23. 23.
    Thome JJ, Yudanin N, Ohmura Y, Kubota M, Grinshpun B, Sathaliyawala T, Kato T, Lerner H, Shen Y, Farber DL (2014) Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159:814–828CrossRefGoogle Scholar
  24. 24.
    Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K (2005) Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol 175:3262–3267CrossRefGoogle Scholar
  25. 25.
    McElhaney JE, Zhou X, Talbot HK, Soethout E, Bleackley RC, Granville DJ, Pawelec G (2012) 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 30:2060–2067CrossRefGoogle Scholar
  26. 26.
    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, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefGoogle Scholar
  27. 27.
    Kelderman S, Heemskerk B, van Tinteren H, van den Brom RR, Hospers GA, van den Eertwegh AJ, Kapiteijn EW, de Groot JW, Soetekouw P, Jansen RL, Fiets E, Furness AJ, Renn A, Krzystanek M, Szallasi Z, Lorigan P, Gore ME, Schumacher TN, Haanen JB, Larkin JM, Blank CU (2014) Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 63:449–458Google Scholar
  28. 28.
    Chiarion Sileni V, Pigozzo J, Ascierto PA, Grimaldi AM, Maio M, Di Guardo L, Marchetti P, de Rosa F, Nuzzo C, Testori A, Cocorocchio E, Bernengo MG, Guida M, Marconcini R, Merelli B, Parmiani G, Rinaldi G, Aglietta M, Grosso M, Queirolo P (2014) Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme. J Exp Clin Cancer Res 33:30CrossRefGoogle Scholar
  29. 29.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, K.-. investigators (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532CrossRefGoogle Scholar
  30. 30.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefGoogle Scholar
  31. 31.
    Ibrahim T, Mateus C, Baz M, Robert C (2018) Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study. Cancer Immunol Immunother (in press)Google Scholar
  32. 32.
    Kugel CH, Webster MR, Kaur A, Liu Q, Yin X et al (2018) Age correlates with response to anti-PD-1, reflecting age-related differences un intra-tumoral effector and regulatory T cell populations. Clin Cancer Res.
  33. 33.
    Alkharabsheh O, Kannarkatt P, Kannarkatt J, Karapetyan L, Laird-Fick HS, Al-Janadi A (2018) An overview of the toxicities of checkpoint inhibitors in older patients with cancer. J Geriatr Oncol.
  34. 34.
    Mian I, Yang M, Zhao H, Shah M, Diab A, Shannon V, Patel A, Amaria RN, Giordano SH, Suarez-Almazor ME (2016) Immune-related adverse events and survival in elderly patients with melanoma treated with ipilimumab. J Clin Oncol 34:3047–3047CrossRefGoogle Scholar
  35. 35.
    Leroy V, Dutriaux C, Prey S,Gey A, Gerard E, Mertens C, Beylot-Barry M, Pham-Ledard A (2018) Adverse events, hospitalization-need and systemic immunosuppression in very elderly adults (80+) treated with ipilimumab for metastatic melanoma. Cancer Immunol Immunother (in press)Google Scholar
  36. 36.
    Friedman CF, Horvat TZ, Minehart J, Panageas K, Callahan MK, Chapman PB (2016) Efficacy and safety of checkpoint blockade for treatment of advanced melanoma in patients age 80 and older. J Clin Oncol 34:10009CrossRefGoogle Scholar
  37. 37.
    Nishijima TF, Muss HB, Shachar SS, Moschos SJ (2016) Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev 45:30–37CrossRefGoogle Scholar
  38. 38.
    Elias R, Giobbie-Hurder A, McCleary NJ, Ott P, Hodi FS, Rahma O (2018) Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J Immunother Cancer 6:26CrossRefGoogle Scholar
  39. 39.
    Herin H, Aspeslagh S, Castanon E, Dyevre V, Marabelle A, Varga A, Postel Vinay S, Michot JM, Ribrag V, Gazzah A, Bahleda R, Mir O, Massard C, Hollebecque A, Soria JC, Baldini C (2018) Immunotherapy phase I trials in patients older than 70 years with advanced solid tumours. Eur J Cancer 95:68–74CrossRefGoogle Scholar
  40. 40.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639CrossRefGoogle Scholar
  41. 41.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate I (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813CrossRefGoogle Scholar
  42. 42.
    Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16:257–265CrossRefGoogle Scholar
  43. 43.
    Ferrara R, Mezquita L, Auclin E, Chaput N, Besse B (2017) Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: does age really matter? Cancer Treat Rev 60:60–68CrossRefGoogle Scholar
  44. 44.
    Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA, Wong P, Romano E, Khammari A, Dreno B, Capone M, Ascierto PA, Di Giacomo AM, Maio M, Schilling B, Sucker A, Schadendorf D, Hassel JC, Eigentler TK, Martus P, Wolchok JD, Blank C, Pawelec G, Garbe C, Weide B (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 22:2908–2918CrossRefGoogle Scholar
  45. 45.
    Martens A, Wistuba-Hamprecht K, Yuan J, Postow MA, Wong P, Capone M, Madonna G, Khammari A, Schilling B, Sucker A, Schadendorf D, Martus P, Dreno B, Ascierto PA, Wolchok JD, Pawelec G, Garbe C, Weide B (2016) Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab. Clin Cancer Res 22:4848–4858CrossRefGoogle Scholar
  46. 46.
    Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217–221CrossRefGoogle Scholar
  47. 47.
    Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Lower M, Bukur V, Tadmor AD, Luxemburger U, Schrors B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Muller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Bruck AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Holler C, Utikal J, Huber C, Loquai C, Tureci O (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547:222–226CrossRefGoogle Scholar
  48. 48.
    Schulz AR, Malzer JN, Domingo C, Jurchott K, Grutzkau A, Babel N, Nienen M, Jelinek T, Niedrig M, Thiel A (2015) Low thymic activity and dendritic cell numbers are associated with the immune response to primary viral infection in elderly humans. J Immunol 195:4699–4711CrossRefGoogle Scholar
  49. 49.
    Bailur JK, Gueckel B, Derhovanessian E, Pawelec G (2015) 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 17:34CrossRefGoogle Scholar
  50. 50.
    Kini Bailur J, Gueckel B, Pawelec G (2016) Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer. J Transl Med 14:151CrossRefGoogle Scholar
  51. 51.
    Hegde UP, Mukherji B (2017) Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies. Cancer Immunol Immunother 66:1113–1121CrossRefGoogle Scholar
  52. 52.
    Stronen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, Donia M, Boschen ML, Lund-Johansen F, Olweus J, Schumacher TN (2016) Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352:1337–1341CrossRefGoogle Scholar
  53. 53.
    Kohn CG, Zeichner SB, Chen Q, Montero AJ, Goldstein DA, Flowers CR (2017) Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma. J Clin Oncol 35:1194–1202CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Second Department of Internal MedicineUniversity of TübingenTübingenGermany
  2. 2.Cancer Solutions ProgramHealth Sciences North Research InstituteSudburyCanada

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