Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MULTIPLE MYELOMA, GAMMOPATHIES

Immune senescence in multiple myeloma—a role for mitochondrial dysfunction?

Abstract

Age-related immune dysfunction is primarily mediated by immunosenescence which results in ineffective clearance of infective pathogens, poor vaccine responses and increased susceptibility to multi-morbidities. Immunosenescence-related immunometabolic abnormalities are associated with accelerated aging, an inflammatory immune response (inflammaging) and ultimately frailty syndromes. In addition, several conditions can accelerate the development of immunosenescence, including cancer. This is a bi-directional interaction since inflammaging may create a permissive environment for tumour development. Multiple myeloma (MM) is a mature B-cell malignancy that presents in the older population. MM exemplifies the interaction of age- (Host Response Biology; HRB) and disease-related immunological dysfunction, contributing to the development of a frailty syndrome which impairs the therapeutic impact of recent advances in treatment strategies. Understanding the mechanisms by which accelerated immunological aging is induced and the ways in which a tumour such as MM influences this process is key to overcoming therapeutic barriers. A link between cellular mitochondrial dysfunction and the acquisition of an abnormal immune phenotype has recently been described and has widespread physiological consequence beyond the impact on the immune system. Here we outline our current understanding of normal immune aging, describe the mechanism of immunometabolic dysfunction in accelerating this process, and propose the role these processes are playing in the pathogenesis of MM.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Malignant plasma cells can influence T cell mitochondrial function via both direct and indirect mechanisms.

References

  1. Pawlyn C, Cairns D, Kaiser M, Striha A, Jones J, Shah V, et al. The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial. Leukemia 2020;34:604–12.

    CAS  PubMed  Article  Google Scholar 

  2. O’Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–56.

    CAS  PubMed  Article  Google Scholar 

  4. Mitchell WA, Lang PO, Aspinall R. Tracing thymic output in older individuals. Clin Exp Immunol. 2010;161:497–503.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Nasi M, Troiano L, Lugli E, Pinti M, Ferraresi R, Monterastelli E, et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell. 2006;5:167–75.

    CAS  PubMed  Article  Google Scholar 

  6. Strindhall J, Skog M, Ernerudh J, Bengner M, Löfgren S, Matussek A, et al. The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age. 2013;35:985–91.

    CAS  PubMed  Article  Google Scholar 

  7. Hu B, Li G, Ye Z, Gustafson CE, Tian L, Weyand CM, et al. Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation. Aging Cell. 2019;18:e12957.

    PubMed  PubMed Central  Google Scholar 

  8. Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192:2689–98.

    CAS  PubMed  Article  Google Scholar 

  9. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol. 2002;169:1984–92.

    CAS  PubMed  Article  Google Scholar 

  10. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Zediak VP, Maillard I, Bhandoola A. Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood 2007;110:1161–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci USA. 2011;108:20012–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Fidler TP, Xue C, Yalcinkaya M, Hardaway B, Abramowicz S, Xiao T, et al. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 2021;592:296–301.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl J Med. 2017;377:111–21.

    PubMed  PubMed Central  Article  Google Scholar 

  15. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 2009;460:259–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Morris EV, Edwards CM. Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma. J Cell Physiol. 2018;233:9159–66.

    CAS  PubMed  Article  Google Scholar 

  17. Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank A-M, Bocian C, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20:771–.e6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Liu M, Huo YR, Wang J, Wang C, Liu S, Liu S, et al. Telomere shortening in Alzheimer’s disease patients. Ann Clin Lab Sci. 2016;46:260–5.

    CAS  PubMed  Google Scholar 

  19. Kuszel L, Trzeciak T, Richter M, Czarny-Ratajczak M. Osteoarthritis and telomere shortening. J Appl Genet. 2015;56:169–76.

    CAS  PubMed  Article  Google Scholar 

  20. Zhan Y, Hägg S. Telomere length and cardiovascular disease risk. Curr Opin Cardiol. 2019;34:270–4.

    PubMed  Article  Google Scholar 

  21. Sanderson SL, Simon AK. In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. Aging Cell. 2017;16:1234–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Benetos A, Lai T-P, Toupance S, Labat C, Verhulst S, Gautier S, et al. The nexus between telomere length and lymphocyte count in seniors hospitalized with COVID-19. J Gerontol A Biol Sci Med Sci. 2021;76:e97–101.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, Wu J, et al. An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res. 2016;2016:8426874.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Stevenson AJ, McCartney DL, Harris SE, Taylor AM, Redmond P, Starr JM, et al. Trajectories of inflammatory biomarkers over the eighth decade and their associations with immune cell profiles and epigenetic ageing. Clin Epigenetics. 2018;10:159.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Whiting CC, Siebert J, Newman AM, Du H-W, Alizadeh AA, Goronzy J, et al. Large-scale and comprehensive immune profiling and functional analysis of normal human aging. PLoS One. 2015;10:e0133627.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Alvarez-Rodríguez L, López-Hoyos M, Muñoz-Cacho P, Martínez-Taboada VM. Aging is associated with circulating cytokine dysregulation. Cell Immunol. 2012;273:124–32.

    PubMed  Article  CAS  Google Scholar 

  27. Valletta S, Thomas A, Meng Y, Ren X, Drissen R, Sengül H, et al. Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing. Nat Commun. 2020;11:4075.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Challen GA, Boles NC, Chambers SM, Goodell MA. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 2010;6:265–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Coppé J-P, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.

    PubMed  Article  CAS  Google Scholar 

  30. Ray D, Yung R. Immune senescence, epigenetics and autoimmunity. Clin Immunol. 2018;196:59–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15:505–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14:576–90.

    CAS  PubMed  Article  Google Scholar 

  33. Wagner A, Weinberger B. Vaccines to prevent infectious diseases in the older population: immunological challenges and future perspectives. Front Immunol. 2020;11:717.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Kline KA, Bowdish DME. Infection in an aging population. Curr Opin Microbiol. 2016;29:63–7.

    PubMed  Article  Google Scholar 

  35. Boren E, Gershwin ME. Inflamm-aging: autoimmunity, and the immune-risk phenotype. Autoimmun Rev. 2004;3:401–6.

    CAS  PubMed  Article  Google Scholar 

  36. Gammage PA, Frezza C. Mitochondrial DNA: the overlooked oncogenome? BMC Biol. 2019;17:53.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Bahat A, MacVicar T, Langer T. Metabolism and Innate Immunity Meet at the Mitochondria. Front Cell Dev Biol. 2021;9:720490.

  38. Desdín-Micó G, Soto-Heredero G, Mittelbrunn M. Mitochondrial activity in T cells. Mitochondrion 2018;41:51–7.

    PubMed  Article  CAS  Google Scholar 

  39. Picca A, Lezza AMS, Leeuwenburgh C, Pesce V, Calvani R, Landi F, et al. Fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets. Int J Mol Sci. 2017;18:933.

  40. Dong Z, Pu L, Cui H. Mitoepigenetics and its emerging roles in cancer. Front Cell Dev Biol. 2020;8:4.

    PubMed  PubMed Central  Article  Google Scholar 

  41. Banoth B, Cassel SL. Mitochondria in innate immune signaling. Transl Res. 2018;202:52–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Kim Y, Triolo M, Hood DA. Impact of aging and exercise on mitochondrial quality control in skeletal muscle. Oxid Med Cell Longev. 2017;2017:3165396.

    PubMed  PubMed Central  Google Scholar 

  43. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol. 2005;25:6225–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Callender LA, Carroll EC, Bober EA, Akbar AN, Solito E, Henson SM. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell. 2020;19:e13067.

  45. Baixauli F, Acín-Pérez R, Villarroya-Beltrí C, Mazzeo C, Nuñez-Andrade N, Gabandé-Rodriguez E, et al. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab. 2015;22:485–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Desdín-Micó G, Soto-Heredero G, Aranda JF, Oller J, Carrasco E, Gabandé-Rodríguez E, et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 2020;368:1371–6.

    PubMed  Article  CAS  Google Scholar 

  47. Bryant C, Suen H, Brown R, Yang S, Favaloro J, Aklilu E, et al. Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance. Blood. Cancer J. 2013;3:e148.

    CAS  Google Scholar 

  48. Massaia M, Dianzani U, Bianchi A, Camponi A, Boccadoro M, Pileri A. Defective generation of alloreactive cytotoxic T lymphocytes (CTL) in human monoclonal gammopathies. Clin Exp Immunol. 1988;73:214–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ, et al. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol. 2009;144:686–95.

    PubMed  Article  Google Scholar 

  50. Suen H, Brown R, Yang S, Weatherburn C, Ho PJ, Woodland N, et al. Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade. Leukemia 2016;30:1716–24.

    CAS  PubMed  Article  Google Scholar 

  51. Cook G, Larocca A, Facon T, Zweegman S, Engelhardt M. Defining the vulnerable patient with myeloma-a frailty position paper of the European Myeloma Network. Leukemia 2020;34:2285–94.

    PubMed  PubMed Central  Article  Google Scholar 

  52. Cook G, Royle K-L, Pawlyn C, Hockaday A, Shah V, Kaiser MF, et al. A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation study. Lancet Haematol. 2019;6:e154–66.

    PubMed  PubMed Central  Article  Google Scholar 

  53. Ludwig C, Williams DS, Bartlett DB, Essex SJ, McNee G, Allwood JW, et al. Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma. Blood Cancer J. 2015;5:e359.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 2012;338:1220–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2012;56:1342–51.

    CAS  PubMed  Article  Google Scholar 

  56. Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol. 2009;83:9122–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Li L, Wan S, Tao K, Wang G, Zhao E. KLRG1 restricts memory T cell antitumor immunity. Oncotarget 2016;7:61670–8.

    PubMed  PubMed Central  Article  Google Scholar 

  58. Henson SM, Franzese O, Macaulay R, Libri V, Azevedo RI, Kiani-Alikhan S, et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 2009;113:6619–28.

    CAS  PubMed  Article  Google Scholar 

  59. Bi E, Li R, Bover LC, Li H, Su P, Ma X, et al. E-cadherin expression on multiple myeloma cells activates tumor-promoting properties in plasmacytoid DCs. J Clin Invest. 2018;128:4821–31.

    PubMed  PubMed Central  Article  Google Scholar 

  60. Syrigos KN, Harrington KJ, Karayiannakis AJ, Baibas N, Katirtzoglou N, Roussou P. Circulating soluble E-cadherin levels are of prognostic significance in patients with multiple myeloma. Anticancer Res. 2004;24:2027–31.

  61. Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, et al. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci USA. 2010;107:16601–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Stiles BL. PI-3-K and AKT: Onto the mitochondria. Adv Drug Deliv Rev. 2009;61:1276–82.

    CAS  PubMed  Article  Google Scholar 

  63. An G, Acharya C, Feng X, Wen K, Zhong M, Zhang L, et al. Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 2016;128:1590–603.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Lee MJ, Yun SJ, Lee B, Jeong E, Yoon G, Kim K, et al. Association of TIM-3 expression with glucose metabolism in Jurkat T cells. BMC Immunol. 2020;21:48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Koundouros N, Poulogiannis G. Phosphoinositide 3-Kinase/Akt signaling and redox metabolism in cancer. Front Oncol. 2018;8:160.

    PubMed  PubMed Central  Article  Google Scholar 

  66. Goo CK, Lim HY, Ho QS, Too H-P, Clement M-V, Wong KP. PTEN/Akt signaling controls mitochondrial respiratory capacity through 4E-BP1. PLoS One. 2012;7:e45806.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Cai WJ, Chen Y, Shi LX, Cheng HR, Banda I, Ji YH, et al. AKT-GSK3β signaling pathway regulates mitochondrial dysfunction-associated OPA1 cleavage contributing to osteoblast apoptosis: preventative effects of hydroxytyrosol. Oxid Med Cell Longev. 2019;2019:4101738.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Abu Eid R, Friedman KM, Mkrtichyan M, Walens A, King W, Janik J, et al. Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+ T-cell proliferation and survival. Oncoimmunology 2015;4:e1005448.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. Treon SP, Maimonis P, Bua D, Young G, Raje N, Mollick J, et al. Elevated soluble MUC1 levels and decreased anti-MUC1 antibody levels in patients with multiple myeloma. Blood 2000;96:3147–53.

    CAS  PubMed  Article  Google Scholar 

  70. Chan AK, Lockhart DC, von Bernstorff W, Spanjaard RA, Joo HG, Eberlein TJ, et al. Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation. Int J Cancer. 1999;82:721–6.

    CAS  PubMed  Article  Google Scholar 

  71. Ren J, Bharti A, Raina D, Chen W, Ahmad R, Kufe D. MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 2006;25:20–31.

    CAS  PubMed  Article  Google Scholar 

  72. Zheng MM, Zhang Z, Bemis K, Belch AR, Pilarski LM, Shively JE, et al. The systemic cytokine environment is permanently altered in multiple myeloma. PLoS One. 2013;8:e58504.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Li Y, Li D, Yan Z, Qi K, Chen L, Zhang Z, et al. Potential relationship and clinical significance of miRNAs and Th17 cytokines in patients with multiple myeloma. Leuk Res. 2014;38:1130–5.

    CAS  PubMed  Article  Google Scholar 

  74. Gu J, Huang X, Zhang Y, Bao C, Zhou Z, Jin J. Cytokine profiles in patients with newly diagnosed multiple myeloma: Survival is associated with IL-6 and IL-17A levels. Cytokine 2021;138:155358.

    CAS  PubMed  Article  Google Scholar 

  75. Zingone A, Wang W, Corrigan-Cummins M, Wu SP, Plyler R, Korde N, et al. Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease. Cytokine 2014;69:294–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Jasrotia S, Gupta R, Sharma A, Halder A, Kumar L. Cytokine profile in multiple myeloma. Cytokine 2020;136:155271.

    CAS  PubMed  Article  Google Scholar 

  77. Cook G, Campbell JD, Carr CE, Boyd KS, Franklin IM. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol. 1999;66:981–8.

    CAS  PubMed  Article  Google Scholar 

  78. Campbell JD, Cook G, Robertson SE, Fraser A, Boyd KS, Gracie JA, et al. Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15. J Immunol. 2001;167:553–61.

    CAS  PubMed  Article  Google Scholar 

  79. Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W, et al. Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood 2010;115:5385–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Slattery K, Gardiner CM. NK Cell Metabolism and TGFβ—Implications for Immunotherapy. Front Immunol. 2019;10:2915.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Dimeloe S, Gubser P, Loeliger J, Frick C, Develioglu L, Fischer M, et al. Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells. Sci Signal. 2019;12:3334.

  82. Chang C-J, Liao C-H, Wang F-H, Lin C-M. Transforming growth factor-beta induces apoptosis in antigen-specific CD4+ T cells prepared for adoptive immunotherapy. Immunol Lett. 2003;86:37–43.

    CAS  PubMed  Article  Google Scholar 

  83. Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 2014;35:51–60.

    CAS  PubMed  Article  Google Scholar 

  84. Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology 2007;120:435–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institute for Health Research (NIHR) infrastructure at Leeds, UK. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Author information

Authors and Affiliations

Authors

Contributions

FS and GC designed the manuscript content. FS wrote the first draft. FS, JC, CT, CP, GC edited and produced the final draft for submission.

Corresponding author

Correspondence to Frances Seymour.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Seymour, F., Carmichael, J., Taylor, C. et al. Immune senescence in multiple myeloma—a role for mitochondrial dysfunction?. Leukemia (2022). https://doi.org/10.1038/s41375-022-01653-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41375-022-01653-7

Search

Quick links