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. 2020 Dec 23;11:608849. doi: 10.3389/fimmu.2020.608849

Figure 1.

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.