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NK cells and cancer: you can teach innate cells new tricks

Key Points

  • Natural killer (NK) cells have a primordial role in tumour immunosurveillance. Given their potent antitumour activity, therapeutic manipulation of NK cells provides an attractive strategy for cancer treatment.

  • A balance of inhibitory and stimulatory signals delivered by numerous receptors regulates NK cell functions (cytotoxicity, cytokine production and proliferation). NKG2D is the best characterized of these activating receptors and is directly involved in the recognition of tumours that express NKG2D ligands.

  • NK cells detect and eliminate tumour cells that are deficient in major histocompatibility complex (MHC) class I molecules (missing self), have upregulated stress ligands that are recognized by activating NK cell receptors (induced self), or are coated with antibodies specific for tumour antigens, enabling recognition by NK cells expressing the CD16 Fc receptor, which triggers antibody-dependent cell-mediated cytotoxicity.

  • Immunoediting of tumour cells by NK cells leads to tumour variants that can evade NK cell-mediated responses. Direct and indirect tumour escape mechanisms include secretion of immunosuppressive factors, shedding of ligands for the activating NK cell receptors and induction of ligands for activating NK cell receptors on healthy cells that can serve as decoys.

  • Current checkpoint blockade agents used to activate T cells in cancer patients, such as antibodies against PD1, may also target NK cells. Checkpoint blockade targeting inhibitory receptors shared by NK cells and T cells are currently under clinical evaluation.

  • In addition to engineered T cells, NK cells and their receptors represent an attractive alternative for the use of chimeric antigen receptors.

  • Immunotherapeutic approaches such as the generation of bispecific linkers that engage activating NK cell receptors and tumour-specific antigens are also being developed to unleash the antitumour potential of NK cells.

Abstract

Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for targeting NK cells in the treatment of cancer.

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Figure 1: Schematic representation of physiological NK cell functions.
Figure 2: Schematic representations of immune escape mechanisms used by tumour cells.
Figure 3: Schematic representation of therapeutic approaches that take advantage of NK cell potential.
Figure 4: Schematic representation summarizing the different NK cell-based therapeutic approaches.

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Acknowledgements

L.L.L. is an American Cancer Society professor and is funded by US National Institutes of Health grants AI066897 and AI068129. M.G.M. is a postdoctoral fellow and is funded by the Department of Defense Congressionally Directed Breast Cancer Research Program award W81XWH-13-1-0041.

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Correspondence to Lewis L. Lanier.

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L.L.L and the University of California San Francisco have licensed intellectual property rights regarding NKG2D for commercial applications. M.G.M. declares no competing interests.

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Glossary

Innate lymphoid cell

(ILC). A lymphocyte that participates in the innate immune responses. ILCs are present in RAG-deficient (Rag1−/− and Rag2−/−) mice, so do not require gene rearrangement for their development or recognition.

Natural cytotoxicity receptors

(NCRs). A family of activating receptors expressed by NK cells and some innate lymphoid cells that recognize various, mostly ill-defined, ligands. The three members of this family in humans are NKp46 (encoded by NCR1), NKp44 (encoded by NCR2) and NKp30 (encoded by NCR3). Mice possess only a functional Ncr1 gene and not orthologues of NKp30 or NKp44.

γδT cells

A subset of T cells that express a distinct T cell receptor (TCR) composed of one γ-chain and one δ-chain, instead of the α- and β-chains that comprise the TCR on the majority of T cells. Like natural killer cells, they are considered to be a bridge between innate and adaptive immunity.

Chédiak–Higashi syndrome and X-linked lymphoproliferative syndrome

Autosomal recessive genetic disorders that impair natural killer cell and T cell effector functions.

Invariant natural killer T cells

(iNKT cells). A subset of T cells that express certain natural killer cell markers as well as an invariant T cell receptor α-chain. Their recognition is restricted to glycolipids presented by the CD1d antigen-presenting molecule.

Lymphokine-activated killer cells

(LAK cells). Cytolytic lymphocytes, predominantly natural killer cells, that have been generated after stimulation with interleukin-2 and can spontaneously lyse cancer cells.

Alloantigen-specific response

An immune response directed towards polymorphic antigens expressed by cells of the same species, such as those from transplanted cells or tissues.

Graft-versus-host disease

(GVHD). A complication of allogeneic haematopoietic stem cell transplantation that occurs when contaminating T cells present in the graft recognize the recipient cells as foreign and mount an immune response against them.

Adoptive cell transfer

Refers to the administration of autologous or allogeneic cells to a recipient.

Anergic state

Characterized by the unresponsiveness of immune cells as a result of chronic stimulation or other immunosuppressive mechanisms.

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Morvan, M., Lanier, L. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16, 7–19 (2016). https://doi.org/10.1038/nrc.2015.5

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