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Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy

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Abstract

The incidence of some types of tumours has increased progressively in recent years and is expected to continue growing in the coming years due in part to the aging of the population. The design of new therapies based on natural killer (NK) cells opens new possibilities especially for the treatment of elderly patients who are particularly susceptible to the toxicity of conventional chemotherapy treatments. In recent years, the potential use of NK cells in cancer immunotherapy has been of great interest thanks to advances in the study of NK cell biology. The identification of key points (checkpoints) in the activation of NK cells that can be regulated by monoclonal antibodies has allowed the design of new therapeutic strategies based on NK cells. However, there are still limitations for its use and the first clinical trials blocking KIR inhibitory receptors have shown little efficacy by inhibiting the maturation of NK cells. Blockade of other inhibitory receptors such as TIGIT, TIM3, LAG3 and PD1 may represent novel strategies to increase NK function in cancer patients. Altogether, the identification of NK cell and tumour cell markers of resistance or susceptibility to the action of NK cells will contribute to identifying those patients that will most likely benefit from NK cell-based immunotherapy.

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Abbreviations

AML:

Acute myeloid leukaemia

CAR:

Chimeric antigen receptor

CTL:

Cytotoxic T lymphocytes

HLA:

Human leukocyte antigen

IFN:

Interferon

IL:

Interleukin

KIR:

Killer cell immunoglobulin-like receptors

LAG-3:

Lymphocyte activating gene 3

MHC:

Major histocompatibility complex

miRNAs:

MicroRNAs

mAb:

Monoclonal antibody

NCRs:

Natural cytotoxicity receptors

NK:

Natural killer

NSCLC:

Non-small cell lung cancer

PD-1:

Programmed death-1

TIM-3:

T cell immunoglobulin and mucin domain 3

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

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Funding

This work was supported by Grants PI13/02691 (to Rafael Solana), PI16/01615 (to Rafael Solana and Corona Alonso) by Instituto de Salud Carlos III, SAF2013-46161-R and SAF2017-87538-R (to Raquel Tarazona) from the Agencia Estatal de Investigacion (Ministry of Economy and Competitiveness of Spain), IB16164 and Grants to INPATT (CTS040) research group (GR18085) from Consejeria de Economia e Infraestructura (Junta de Extremadura) (to Raquel Tarazona), cofinanced by European Regional Development Funds (FEDER) “Una manera de hacer Europa”.

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Author notes

  1. Rafael Solana and Raquel Tarazona are senior authors and have contributed equally to the manuscript.

Authors and Affiliations

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

    Beatriz Sanchez-Correa, Nelson Lopez-Sejas & Raquel Tarazona

  2. Histology and Pathology Unit, Faculty of Veterinary, University of Extremadura, Caceres, Spain

    Esther Duran

  3. Immunology Unit, Universidad de Cordoba, Cordoba, Spain

    Fernando Labella & Rafael Solana

  4. Instituto Maimónides de Investigación Biomédica (IMIBIC), Córdoba, Spain

    Corona Alonso & Rafael Solana

  5. Reina Sofia University Hospital, Córdoba, Spain

    Corona Alonso & Rafael Solana

Authors
  1. Beatriz Sanchez-Correa
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  2. Nelson Lopez-Sejas
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  3. Esther Duran
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  4. Fernando Labella
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  5. Corona Alonso
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  6. Rafael Solana
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  7. Raquel Tarazona
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Contributions

BS-C, RS and RT designed and wrote the first draft of the manuscript. NL-S, ED, FL and CA discussed the manuscript sections and contributed with updated references. All authors revised and agreed the final version of the paper.

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Correspondence to Rafael Solana.

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Sanchez-Correa, B., Lopez-Sejas, N., Duran, E. et al. Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy. Cancer Immunol Immunother 68, 861–870 (2019). https://doi.org/10.1007/s00262-019-02336-6

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  • DOI: https://doi.org/10.1007/s00262-019-02336-6

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