Immunosurveillance. The term immunosurveillance refers to a series of processes whereby the immune system spontaneously patrols for, recognises, and eradicates neoplastic cells before they become tumours. This phenomenon has been clearly demonstrated through evidence of increased numbers of tumours in immune-deficient humans and mice (Xxxx et al., 2004). Immunosurveillance is thought to be the principle function of an innate immune cell type called natural killer (NK) cells. Like certain T cells types, these cells are activated by the cytokines IL-2, IL-12, IL-15 and type 1 interferons, and migrate into tumourigenic environments in response to chemokines CCL2 and CCL5 (Xxxxxxxxxx et al., 2012, Zwirner and Xxxxxxx, 2010). NK cells are able to mediate cellular killing through i) the release of cytotoxic granules containing perforin and granzyme, ii) the ligation of death receptors such as TNF, FasL and TRAIL, to induce apoptosis, or iii) the expression of IFNγ, which halts tumour growth and induces the activation of other immune compartments (Zwirner and Xxxxxxx, 2010). Key to the function of NK cells is their ability to distinguish transformed cells from healthy cells. They do this through the recognition of a number of stress induced molecules on the surface of tumour cells which bind and activate a highly redundant series of receptors on the NK surface, most notably NKG2D (Long et al., 2013). NK cells require ligation of the inhibitory KIR receptor (Ly49 in mice) by MHC class 1 on the target cell surface to provide a ‘do not kill’ signal. In the presence of other stimulatory signals from the target cell, the failure to detect MHC class 1 leads to the activation of second pathway, and the tumour cell is perceived as non-self, and subsequently destroyed (Xxxx et al., 2013). An increasing body of evidence in mice supports the concept of NK cells as the natural mediators of immunosurveillance. For example, RAG-/- mice, which lack adaptive immunity, developed far fewer tumours than RAG-/- and γc-/- mice, which lack both adaptive immunity and NK cells (X'Xxxxxxxx et al., 2012). Further evidence comes from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer. TRAMP mice spontaneously develop prostate adenocarcinoma at puberty due to the transgenic expression of the SV40 large T antigen under control of the prostate specific probasin promoter (Xxxxxxx et al., 2001). Augmented tumour growth was observed in TRAMP mice which were also deficient for the N...
