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Immunosenescence: limitations of natural killer cell-based cancer immunotherapy

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Abstract

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.

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Abbreviations

ADCC:

Antibody-dependent cell cytotoxicity

AML:

Acute myeloid leukaemia

CAR:

Chimeric antigen receptor

CMV:

Cytomegalovirus

DNAM-1:

DNAX accessory molecule-1

HLA:

Human leucocyte antigen

HMGB1:

High-mobility group protein B1

IFN:

Interferon

IL:

Interleukin

KIR:

Killer cell immunoglobulin-like receptors

Lag-3:

Lymphocyte-activating gene 3

LAK:

Lymphokine-activated killer

LILRB1:

Leucocyte immunoglobulin-like receptor subfamily B member 1

mAb:

Monoclonal antibody

MHC:

Major histocompatibility complex

miRNAs:

MicroRNAs

NCRs:

Natural cytotoxicity receptors

NK:

Natural killer

SEB:

Staphylococcal enterotoxin B

TGF:

Tumour growth factor

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

Tim-3:

T cell immunoglobulin and mucin domain 3

TNF:

Tumour necrosis factor

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Acknowledgments

We apologize to our colleagues whose work was not cited due to space limitations. This work was supported by Grants SAF2009-09711 and SAF2013-46161-R (to Raquel Tarazona) from the Ministry of Economy and Competitiveness of Spain, PS09/00723 and PI13/02691 (to Rafael Solana) from Spanish Ministry of Health, CTS-208 from Junta de Andalucia (to Rafael Solana) and grants to INPATT research group from Junta de Extremadura (GRU15183) and University of Extremadura (to Raquel Tarazona and Esther Duran) co-financed by European Regional Development Funds (FEDER).

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Author notes

  1. Javier G. Casado

    Present address: Stem Cell Therapy Unit, Minimally Invasive Surgery Centre Jesus Uson, Cáceres, Spain

  2. Alejandra Pera

    Present address: Brighton and Sussex Medical School, University of Sussex, Brighton, UK

Authors and Affiliations

  1. Immunology Unit, University of Extremadura, Cáceres, Spain

    Raquel Tarazona, Beatriz Sanchez-Correa, Sara Morgado & Javier G. Casado

  2. Department of Haematology, Hospital San Pedro de Alcantara, Cáceres, Spain

    Ignacio Casas-Avilés, Juan M. Bergua, Maria Jose Arcos & Helena Bañas

  3. IMIBIC - Reina Sofia University Hospital - University of Cordoba, REIPI, Córdoba, Spain

    Carmen Campos, Alejandra Pera, Nelson López-Sejas, Fakhri Hassouneh, Fernando Labella & Rafael Solana

  4. Histology and Pathology Unit, Faculty of Veterinary, University of Extremadura, Cáceres, Spain

    Esther Durán

  5. Department of Immunology, Facultad de Medicina Universidad de Córdoba, Avenida de Menéndez Pidal s/n, 14004, Córdoba, Spain

    Rafael Solana

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  1. Raquel Tarazona
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  2. Beatriz Sanchez-Correa
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Correspondence to Rafael Solana.

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Additional information

This paper is a Focussed Research Review based on a presentation given at the Fifteenth International Conference on Progress in Vaccination against Cancer (PIVAC 15), held in Tübingen, Germany, 6th–8th October, 2015. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews and meeting report.

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Tarazona, R., Sanchez-Correa, B., Casas-Avilés, I. et al. Immunosenescence: limitations of natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 66, 233–245 (2017). https://doi.org/10.1007/s00262-016-1882-x

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