Natural killer cells and other innate lymphoid cells in cancer

  • A Correction to this article was published on 12 October 2018

Abstract

Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.

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Fig. 1: Cell surface receptors expressed by human and mouse ILCs.
Fig. 2: Crosstalk between natural killer cells and tumour cells.
Fig. 3: Pleiotropic roles of ILC1s, ILC2s and ILC3s in cancer.
Fig. 4: Therapeutic approaches to restore NK cell-mediated tumour cell lysis.

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Acknowledgements

The laboratory of E.V. is supported by funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation programme (Targeting innate lymphoid cells (TILC), grant agreement number 694502); the Agence Nationale de la Recherche, Equipe Labellisée “La Ligue”, Ligue Nationale contre le Cancer, MSDAvenir, Innate Pharma and institutional grants to the CIML (Institut National Français de Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille University) and to Marseille Immunopôle. P.-Y.D. is a fellow of the Fondation de France. M.V. is a recipient of an individual PhD grant from the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation. The authors thank M. Blery, Y. Morel and S. Cornen for helpful comments.

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Nature Reviews Immunology thanks M. Smyth and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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E.V., L.C., P.-Y.D. and M.V. contributed to researching data, discussion of content and the writing of this article. E.V., L.C. and P.-Y.D. reviewed and edited the manuscript.

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Correspondence to Eric Vivier.

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L.C. and E.V. are employees of Innate Pharma. The other authors declare no competing interests.

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Supplementary information

Glossary

Asialo-GM1

The cell surface glycolipid GM1 with its sialic acid groups removed. Asiolo-GM1 is expressed by natural killer cells and also by a subset of T cells and myeloid cells.

NK1.1

An activating C-type lectin receptor that is expressed by natural killer cells and natural killer T cells in C57Bl/6 mice.

Natural killer cell p46-related protein

(NKp46). An activating receptor that is expressed by human and mouse natural killer cells and subsets of group 1 innate lymphoid cells (ILC1s) and ILC3s.

Killer cell immunoglobulin-like receptors

(KIRs). A family of receptors (including CD158) for MHC class I molecules that are expressed on natural killer (NK) cells and a subset of T cells. They regulate NK cell activation and tolerance.

Leukocyte immunoglobulin-like receptor subfamily B member 1

(LIR1). A receptor for a broad range of MHC class I molecules that is expressed by monocytes, natural killer cells, T cells and B cells. Engagement of LIR1 results in inhibitory immune signalling.

The ‘missing ligand’ model

A model that postulates that a natural killer (NK) cell-mediated graft-versus-leukaemia effect will also occur when the donor NK cells express an inhibitory killer cell immunoglobulin-like receptor (KIR) for which neither donor nor recipient expresses a relevant MHC class I ligand.

The ‘donor haplotype’ model

A model suggesting that assessing donor killer cell immunoglobulin-like receptor (KIR) haplotypes is important for determining the efficacy of haematopoietic stem cell transplantation; KIR gene clusters include haplotype A, which contains predominantly inhibitory KIRs, and haplotype B, whose members are more diverse.

CD57

A suggested marker for replicative senescence. CD57 is absent on fetal natural killer (NK) cells, increases with age and defines a subpopulation of highly differentiated circulating NK cells.

Natural cytotoxicity receptors

(NCRs). A family of activating receptors (including natural killer cell p30-related protein (NKp30), NKp44 and NKp46) that is selectively expressed by innate lymphoid cells.

Pomalidomide

An anti-angiogenic and immunomodulatory drug that is a derivative of thalidomide.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of immature myeloid cells that rapidly expand during inflammation and are able to downregulate immune responses.

Amphiregulin

A member of the epidermal growth factor (EGF) family that signals through the EGF receptor (EGFR).

Bispecific killer cell engagers

(BiKEs). Bispecific monoclonal antibodies that bind activating natural killer cell receptors at one end and tumour antigens at the other.

Trispecific killer cell engagers

(TriKEs). Molecules containing two antibody fragments, which are directed against an activating natural killer cell receptor and a tumour antigen, and an immune stimulatory cytokine crosslinker.

Rituximab

A cytotoxic antibody directed against CD20 that destroys both normal and malignant B cells and is therefore used to treat diseases characterized by having too many B cells.

Lenalidomide

A derivative of thalidomide that inhibits tumour angiogenesis and tumour cell proliferation.

Durvalumab

An antibody that blocks programmed cell death 1 ligand 1 (PDL1).

Cetuximab

An antibody that blocks epidermal growth factor receptor (EGFR).

ALT803

An IL-15–IL-15 receptor subunit-α (IL-15Rα) complex fused to an IgG1 crystallizable fragment (Fc) domain; in this construct, IL-15 is additionally mutated to increase its biological activity.

Melphalan

A chemotherapy drug that acts as an alkylating agent.

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Chiossone, L., Dumas, P., Vienne, M. et al. Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol 18, 671–688 (2018). https://doi.org/10.1038/s41577-018-0061-z

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