Control of Metastasis by NK Cells Alejandro López-Soto, Segundo Gonzalez, Mark J. Smyth, Lorenzo Galluzzi  Cancer Cell  Volume 32, Issue 2, Pages 135-154 (August 2017) DOI: 10.1016/j.ccell.2017.06.009 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 The Metastatic Cascade Metastasis involves the detachment of malignant cells from the primary tumor, their intravasation and persistence in the blood as circulating tumor cells (CTCs), their extravasation and persistence at pre-metastatic niches as disseminated tumor cells (DTCs), and eventually their reactivation to generate clinically detectable macrometastatic lesions. Cancer Cell 2017 32, 135-154DOI: (10.1016/j.ccell.2017.06.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Immunosurveillance of Metastasis by NK Cells (A) Normal cells and some malignant cells express multiple ligands for natural killer (NK) cell inhibitory receptors (NKIRs), hence robustly suppressing NK cell activation. (B) However, potentially metastatic cancer cells, including cells that have undergone the epithelial-to-mesenchymal transition, lose the expression of NKIR ligands as they upregulate ligands for NK cell activatory receptors (NKARs). In this setting, NK cells become potently activated to release cytotoxic granules (G) that contain perforin 1 (PRF1) and granzyme B (GRZB), and to secrete interferon gamma (IFNG), hence mediating robust antimetastatic effects. Cancer Cell 2017 32, 135-154DOI: (10.1016/j.ccell.2017.06.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Mechanisms of NK Cell Evasion by Cancer Cells Malignant cells avoid recognition and elimination by natural killer (NK) cells via multiple mechanisms that operate directly on NK cells, upon the activation of immunosuppressive cells, or upon the inhibition of immunostimulatory cells. These mechanisms include (1) upregulation (↑) of NK cell inhibitory receptor (NKIR) ligands; (2) downregulation (↓) of NK cell activatory receptor (NKAR) ligands; (3) downregulation of death receptors; (4) secretion of metalloproteinases that generate soluble NKAR ligands; (5) decreased (↘) secretion of immunostimulatory cytokines; (6) increased (↗) secretion of immunosuppressive cytokines; (7) decreased recruitment of NK cells; (8) increased recruitment of immune cells with immunosuppressive functions; (9) physical coating with platelets; (10) acquisition of a pseudo-self state; (11) hypoxia-dependent extracellular adenosine synthesis; and (12) hypoxia-dependent autophagy activation. Cancer Cell 2017 32, 135-154DOI: (10.1016/j.ccell.2017.06.009) Copyright © 2017 Elsevier Inc. Terms and Conditions