Abstract
Natural killer (NK) cells recognize and kill tumor cells via germ-line encoded receptors and polarized degranulation of cytotoxic molecules, respectively. As such, NK cells help to inhibit the development of cancers. The activating receptor NKG2D induces NK cell-mediated killing of metastasizing tumor cells by recognition of the stress-induced ligands MICA, MICB, and ULBP1-6. However, platelets enable escape from this immune surveillance mechanism by obstructing the interactions between NK cells and tumor cells or by cleaving the stress-induced ligands. It is also being increasingly appreciated that NK cells play additional roles in cancer immunity, including chemokine-mediated recruitment of antigen presenting cells in the tumor microenvironment that is followed by generation of adaptive immunity. However, the NK cell interplays with dendritic cells, and macrophages are extremely complex and involve molecular interactions via NKG2D and cytokine receptors. Specifically, NKG2D-mediated chronic interaction between NK cells and tumor-infiltrating macrophages causes immune suppression by differentiating NK cells toward a dysfunctional state. Here we discuss the underlying mechanisms of NK cell control by platelets and myeloid cells with focus on NKG2D and its ligands, and provide a timely perspective on how to harness these pathways with novel immunotherapeutic approaches.
Highlights
Natural Killer (NK) cells are innate lymphocytes that recognize and kill abnormal cells, such as tumor cells and cells infected by viruses [1]
We recently discovered that tumor cell-associated NKG2D ligands (NKG2DL), predominantly MHC class I polypeptide-related sequence A (MICA) and MHC class I polypeptide-related sequence B (MICB), were cleaved following interaction with platelets or platelet releasate
We demonstrate that platelet-mediated shedding of NKG2DL dampens NK cell antitumor immunity by reducing the activating signals
Summary
Natural Killer (NK) cells are innate lymphocytes that recognize and kill abnormal cells, such as tumor cells and cells infected by viruses [1]. Platelets interfere with the “missing self” recognition of metastatic cells and dampen NK cell-driven anti-tumor immunity via pseudo-expression of “non-malignant” MHC class I. We recently discovered that tumor cell-associated NKG2DL, predominantly MICA and MICB, were cleaved following interaction with platelets or platelet releasate.
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