Figure 2 Immune-escape mechanisms of CTCs in the peripheral blood

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Figure 2 Immune-escape mechanisms of CTCs in the peripheral blood Figure 2 | Immune-escape mechanisms of CTCs in the peripheral blood. The schematic illustrates the potential mechanisms of immune escape of CTCs, and the interactions between CTCs and immune cells in the peripheral blood. The interplay between CTCs and NK cells is highlighted, with secretion of LDH5 and ADAM10- mediated shedding of the NKG2D ligand MICA/MICB from CTCs preventing recognition and elimination of the cells via NK-cell-mediated lysis. LDH5 exerts this effect indirectly by upregulating the expression of NKG2D ligands on circulating monocytes, which results in downregulation of NKG2D expression on NK cells. Three different strategies of CTC escape from MHC I-mediated recognition by NK cells and T cells are depicted: interference with TCR recognition of MHC I molecules by cell-surface-bound cytokeratins (CK8, CD18, and CK19); acquisition of a 'pseudonormal' phenotype resulting from membrane transfer from platelets to CTCs; and the downregulation or loss of MHC I expression. Additional mechanisms of immune escape include expression of the inhibitory immune-checkpoint protein PD-L1, presentation of the 'don't eat me' signalling receptor CD47, and an altered expression of the apoptotic proteins FAS and/or FASL. ADAM10, disintegrin and metalloproteinase domain-containing protein 10; CK8, cytokeratin 8; CK18, cytokeratin 18; CK19, cytokeratin 19; CTC, circulating tumour cell; DC, dendritic cell; FASL, FAS ligand; IL-10, interleukin 10; KIR, killer-cell immunoglobulin-like receptor; LDH5, lactate dehydrogenase 5; MHC I, MHC class I; MICA, MHC I polypeptide-related sequence A; MICB, MHC I polypeptide-related sequence B; NK, natural killer; NKG2D, NK-cell receptor D (also known as NKG2-D type II integral membrane protein); PD-1, programmed cell-death protein 1; PD-L1, programmed cell death 1 ligand 1; PGE2, prostaglandin E2; SIRPα, signal-regulatory protein α; TCR, T-cell receptor; TGFβ, transforming growth factor β; TLR, Toll-like receptor. Mohme, M. et al. (2016) Circulating and disseminated tumour cells — mechanisms of immune surveillance and escape Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.144