Abstract
Natural Killer (NK) cells are cytotoxic lymphocytes that play a key role in the immune system, targeting and destroying invading pathogens and malignantly transformed cells. Evading NK cell-mediated immunosurveillance is therefore critical to facilitating cancer cell survival and metastasis. Signals from a range of inhibitory and activating receptors located on the NK cell surface regulate NK cell cytotoxicity. Recently, attention has turned to the role of hypersialylated tumor cell surfaces in mediating immune-evasion of NK cells. Two inhibitory sialic acid-binding immunoglobulin-like lectin (Siglec) receptors are expressed by NK cells: Siglec-7 and Siglec-9. The abundance of sialic acids on tumor cell surface is hypothesized to regulate NK cell-mediated cytotoxicity by interacting with Siglec-7 and Siglec-9, causing a dampening of NK cell activation pathways. Targeting Siglec-7 and Siglec-9, or the sialic acid coated tumor cell surface is therefore being investigated as a novel therapeutic approach to enhance the NK cell response against cancer. In this review we report on the currently published documentation of the role for Siglec-7 and Siglec-9 receptors on NK cells and their ligands expressed by tumor cells. We also discuss the strategies currently explored to target Siglec-7, Siglec-9 and the sialylated tumor cell surface as well as the impact abrogation of these interactions have on NK cell cytotoxicity against several cancer types.
Highlights
TO NATURAL KILLER CELLS AND MECHANISMS GOVERNING TARGET KILLINGNatural Killer (NK) cells are cytotoxic lymphocytes, constituting 5–15% of peripheral blood lymphocytes [1]
In this review we report on the currently published documentation of the role for sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and Siglec-9 receptors on NK cells and their ligands expressed by tumor cells
There is compelling evidence that the hypersialylated glycan layer on cancer cells plays an important role in facilitating immune evasion
Summary
Natural Killer (NK) cells are cytotoxic lymphocytes, constituting 5–15% of peripheral blood lymphocytes [1]. Based on the originally proposed model for ‘missing-self recognition’, in order to kill a target cell NK cells need activation signals in addition to low or no inhibition during target cell interaction [10] Stressed cells, such as malignantly-transformed cells or virally infected cells, may express and up-regulate the MHC class I chain-related (MIC) ligands MIC-A and MIC-B for the activating natural killer group 2, member D (NKG2D) receptor expressed by NK cells [12]. Target recognition via antibodydependent cellular cytotoxicity (ADCC) triggers strong NK cell activation [21] In this situation, the Fc receptor CD16 (FcyRIIIa) expressed by NK cells binds to the Fc portions of antibodies, triggering NK cell secretion of granzymes and perforin to lyse target cells, as well as cytokines to stimulate the adaptive immune response [22]. It is today clear that the balance between signals from activating and inhibitory receptors on the NK cell surface is crucial for the detection and eradication of malignant cells, while sparing healthy cells
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