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  • Review Article
  • Published:

Oncogenic stress sensed by the immune system: role of natural killer cell receptors

Nature Reviews Immunology volume 9, pages 568–580 (2009)Cite this article

Key Points

  • This Review discusses the foremost genetic and immunological studies that probe the role of natural killer (NK) cells and NK cell receptors in tumour surveillance, and link such responses to specific stress pathways that are activated during the process of tumorigenesis. It also discusses the advantages and shortcomings of models used to investigate tumour immunology in vivo.

  • Recent evidence suggests that cell-intrinsic events, occurring at early stages of tumorigenesis, can activate the immune system and lead to the elimination of nascent tumour cells by innate effector cells.

  • The balance of signalling by stimulatory and inhibitory receptors determines whether NK cells are activated. Stimulatory receptors often recognize self ligands that are expressed selectively by transformed, infected or damaged tissues (induced self recognition), whereas inhibitory receptors recognize ligands, such as MHC class I molecules, that are sometimes lost on the same types of diseased cell (missing self recognition).

  • NKG2D, a well-characterized stimulatory receptor that is expressed by NK cells and some T cells, recognizes several self ligands that are often induced on cancer cells. Evidence has accumulated that NKG2D recognition by NK cells and/or T cells underlies protective immune responses against cancer.

  • Cellular stress pathways that are activated in tumour cells as a consequence of the tumorigenesis process induce the expression of NK cell receptor ligands that target protective NK cell responses. These pathways include the DNA damage response, cell senescence programmes and the heat shock response.

  • Multiple stress pathways must be activated to optimally induce the expression of some NK cell receptor ligands because such ligands are regulated at distinct levels of biogenesis by different stress pathways. This requirement presumably helps to ensure that only unhealthy cells are targeted.

  • Tumours often take evasive action to avoid protective NK cell responses. Among the evasion mechanisms are loss of the corresponding ligands, shedding of such ligands in a manner that systemically inhibits NKG2D responses, persistent stimulation of NK cells and/or T cells in a manner that desensitizes them, or induction of suppressive cytokines.

Abstract

A growing body of research is addressing how pathways that are dysregulated during tumorigenesis are linked to innate immune responses, which can contribute to immune surveillance of cancer. Components of the innate immune system that are localized in tissues are thought to eliminate early neoplastic cells, thereby preventing or delaying the establishment of advanced tumours. This Review addresses our current understanding of the mechanisms that detect cellular stresses that are associated with tumorigenesis and that culminate in the recognition and, in some cases, the elimination of the tumour cells by natural killer cells and other lymphocytes that express natural killer cell receptors.

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Figure 1: Stepwise cancer progression and intrinsic and extrinsic barriers to cancer.
Figure 2: Model of NKG2D-mediated tumour surveillance of prostate adenocarcinoma.

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Acknowledgements

The authors thank laboratory colleagues for advice, collaboration and ideas. The research in the authors' laboratory was supported by grants from the National Institutes of Health and a postdoctoral fellowship from the Cancer Research Institute.

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  1. Department of Molecular and Cell Biology, Cancer Research Laboratory, 485 Life Science Addition, University of California, Berkeley, 94720, California, USA

    David H. Raulet & Nadia Guerra

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Correspondence to David H. Raulet.

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Recombination-activating gene 2

(Rag2). A gene encoding a protein that mediates V(D)J recombination in preB cells and thymocytes, which is necessary for the production of B and T cell receptors, and thus for the development of B and T cells.

Perforin

A component of the cytolytic granules of cytotoxic T cells and natural killer cells that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.

Large T antigen

A multifunctional protein product of the simian virus 40 (SV40) early region that is necessary to establish a permissive host cell environment for viral replication by interactions with host proteins. Large T antigen binds and functionally inactivates the tumour suppressor proteins retinoblastoma and p53.

γδT cell

A T cell that expresses a T cell receptor consisting of a γ-chain and a δ-chain. γδ T cells are present in several epithelial locations as intraepithelial lymphocytes (IELs) and in lymphoid organs. Although the functions of γδ T cells (or IELs) are still mostly unknown, it has been suggested that mucosal γδ T cells mediate innate-type mucosal immune responses, and epidermal γδ T cells in mice have been implicated in tumour surveillance and wound repair.

Natural killer T (NKT) cell

A subpopulation of T cells that expresses both NK cell and T cell markers. In the C57BL/6 mouse strain, NKT cells express the NK1.1 (NKRP1C) molecule and the T cell receptor (TCR). Some NKT cells recognize CD1d-associated lipid antigens and express a restricted repertoire of TCRs (invariant NKT cells). After TCR stimulation of naive cells, NKT cells rapidly produce interleukin-4 and interferon-γ.

NK group 2, member D

(NKG2D). A lectin-type activating receptor encoded by killer cell lectin-like receptor subfamily K, member 1 (Klrk1) located in the natural killer cell gene complex. NKG2D associates with signalling adaptor molecules, including DAP10 (in both humans and mice) and DAP12 (in mice but not humans). DAP10 activates phosphoinositide 3-kinase, and its signalling mechanism resembles that of co-stimulatory receptors, such as CD28. By contrast, DAP12 activates spleen tyrosine kinase, and its signalling resembles that of B and T cell receptors.

Unfolded protein response

A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins and causes cell cycle arrest and apoptosis.

Ataxia telangiectasia

(also known as Louis–Bar syndrome). A familial recessive disease that is characterized by progressive cerebellar ataxia, oculocutaneous telangiectases and susceptibility to pulmonary infections. It is caused by germline mutations in ataxia telangiectasia mutated (ATM), which encodes a sensor that activates the DNA damage response.

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Raulet, D., Guerra, N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9, 568–580 (2009). https://doi.org/10.1038/nri2604

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