Cancer Immunology, Immunotherapy

, Volume 66, Issue 2, pp 233–245 | Cite as

Immunosenescence: limitations of natural killer cell-based cancer immunotherapy

  • Raquel Tarazona
  • Beatriz Sanchez-Correa
  • Ignacio Casas-Avilés
  • Carmen Campos
  • Alejandra Pera
  • Sara Morgado
  • Nelson López-Sejas
  • Fakhri Hassouneh
  • Juan M. Bergua
  • Maria Jose Arcos
  • Helena Bañas
  • Javier G. Casado
  • Esther Durán
  • Fernando Labella
  • Rafael Solana
Focussed Research Review


Cancer is primarily considered a disease of old age. Immunosenescence refers to the age-associated changes in the immune system, and its contribution to the increased risk of cancer in old individuals has been discussed for many years. Natural killer (NK) cells are cytotoxic innate immune cells specialized in defence against tumour and virus-infected cells. NK cell cytotoxicity is the result of a fine balance between activating and inhibitory receptors. Several activating receptors have been identified that recognize different ligands frequently found over-expressed on tumour cells or virus-infected cells. The most important NK cell inhibitory receptors interact with major histocompatibility complex class I molecules expressed on almost all nucleated cells preventing NK cell-mediated lysis of healthy cells. NK cell immunosenescence is characterized by a redistribution of NK cell subsets, a diminished expression of several activating receptors and lower per-cell cytotoxicity. Altered expression of activating receptors has also been described in young and elderly cancer patients probably due to chronic exposure to ligands on tumour cells. Thus, the effect of both age and cancer may act synergistically to diminish NK cell-mediated tumour immunosurveillance. Different strategies harnessing the power of NK cells to target tumour cells have been designed including adoptive therapy with autologous or allogeneic expanded NK cells. In addition, checkpoint blockade of inhibitory receptors and the use of agonist antibodies to stimulate activating receptors are emerging areas of research. In this context, the effect of immunosenescence should be considered to improve the efficiency of cancer immunotherapy.


Ageing Cancer immunotherapy Checkpoint blockade NK cell immunosenescence PIVAC 15 



Antibody-dependent cell cytotoxicity


Acute myeloid leukaemia


Chimeric antigen receptor




DNAX accessory molecule-1


Human leucocyte antigen


High-mobility group protein B1






Killer cell immunoglobulin-like receptors


Lymphocyte-activating gene 3


Lymphokine-activated killer


Leucocyte immunoglobulin-like receptor subfamily B member 1


Monoclonal antibody


Major histocompatibility complex




Natural cytotoxicity receptors


Natural killer


Staphylococcal enterotoxin B


Tumour growth factor


T cell immunoreceptor with Ig and ITIM domains


T cell immunoglobulin and mucin domain 3


Tumour necrosis factor


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Raquel Tarazona
    • 1
  • Beatriz Sanchez-Correa
    • 1
  • Ignacio Casas-Avilés
    • 2
  • Carmen Campos
    • 3
  • Alejandra Pera
    • 3
    • 6
  • Sara Morgado
    • 1
  • Nelson López-Sejas
    • 3
  • Fakhri Hassouneh
    • 3
  • Juan M. Bergua
    • 2
  • Maria Jose Arcos
    • 2
  • Helena Bañas
    • 2
  • Javier G. Casado
    • 1
    • 5
  • Esther Durán
    • 4
  • Fernando Labella
    • 3
  • Rafael Solana
    • 3
    • 7
  1. 1.Immunology UnitUniversity of ExtremaduraCáceresSpain
  2. 2.Department of HaematologyHospital San Pedro de AlcantaraCáceresSpain
  3. 3.IMIBIC - Reina Sofia University Hospital - University of Cordoba, REIPICórdobaSpain
  4. 4.Histology and Pathology Unit, Faculty of VeterinaryUniversity of ExtremaduraCáceresSpain
  5. 5.Stem Cell Therapy UnitMinimally Invasive Surgery Centre Jesus UsonCáceresSpain
  6. 6.Brighton and Sussex Medical SchoolUniversity of SussexBrightonUK
  7. 7.Department of ImmunologyFacultad de Medicina Universidad de CórdobaCórdobaSpain

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