NK Cell Interaction With Platelets and Myeloid Cells in the Tumor Milieu

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.

Keywords: NK cells; NKG2D; myeloid cells; platelets; proteolytic shedding.

Figure 1

Modulation of NK cell reactivity by platelets and myeloid cells. (A) Platelets obstruct NK cells and enable escape of metastasizing tumor cells. Platelets also provide specific immune modulatory molecules like MHC class I which inhibits NK cells. The latter can be transferred into the tumor cell membrane via trogocytosis to inhibit missing self-driven NK cell cytotoxicity. Their cognate Killer-cell immunoglobulin-like receptors (KIRs) inhibit NK antitumor responses upon stimulation. Platelets can also dampen induced self recognition of tumor cells via NKG2D. Platelet-derived metalloproteases (i.e., ADAM10 and ADAM17) cleave NKG2DL from the tumor cell surface. Platelet-released TGF-β also causes NKG2D downregulation, thereby further hindering NK cell antitumor response. (B) The expression of NKG2DL is not restricted to malignant cells. In fact, DC and macrophages can also express NKG2DL upon stimulation or infection, which in-turn induces NK cells to proliferate and produce interferon-γ (IFNG). Virus-infected myeloid cells may become targets and be killed by NK cells upon NKG2D recognition. Intratumoral myeloid cells also express NKG2DL. It is currently unknown what induces NKG2DL expression in intratumoral myeloid cells, yet a potential mechanism is via cellular stress inside the hypoxic tumor microenvironment. These cells benefit tumors by inhibiting NK cells via chronic NKG2D interaction with low affinity ligands, which cause NKG2D internalization.