Fig. 1

Cancer cell immune escape from NK cells during metastasis formation. Schematic representation of the interactions between the TME and NK cells and of some immune evasion mechanisms. The cytotoxic capacity of NK cells can be inhibited by cytokines, such as TGF-β and IL-10, enzymes, such as IDO, or molecules, such as prostaglandin E2, produced by TME cells. Conversely, NK cells activity is promoted by other cytokines present in the TME and secreted by immune cells, such as IL-15, IL-1β, IL-12 and IFN-β. Tumor cell escape is also mediated by direct interactions with NK inhibitory receptors such as NKG2A, PD1, TIGIT, Siglec 7 and 9, and certain KIRS (KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, KIR3DL2). In addition, certain metalloproteases release soluble ligands, such as B7-H6, which bind to the NKp30 activator receptor, thus contributing to NK exhaustion. During tumor progression, some cells detach from the tumor mass and enter the bloodstream. Some CTCs escape NK cell immunosurveillance, particularly by interacting with platelets. For instance, the presence of the platelet-derived RGS18 mRNA on CTCs promote the overexpression of the HLA-E complex. Binding of this complex to the NKG2A/CD94 receptor induces phosphorylation of the tyrosine residues of its ITIM domains that then recruit phosphatases to block NK cell cytotoxic activity. TGF-β secretion by platelets also allows CTCs to escape lysis. Created with BioRender.com. Abbreviations: CTCs, Circulating Tumor Cells; HLA, human leukocyte antigen; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; IFN-β, interferon-β; NET, neutrophil extracellular trap; NKs, natural killers; TGF-β, transforming growth factor β; TME, tumor microenvironnement; IFN-β, interferon-β