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

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Abstract
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.