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. 2018 Feb 14;9:267. doi: 10.3389/fimmu.2018.00267

Figure 1.

Figure 1

Natural killer cell evasion mechanisms in cHL. The accumulation of NK cell evasion mechanisms in cHL TME explains the persistent failure of NK cell infiltration and activity observed in patients. (1) sCD25 blocks IL-2 interaction with IL-2Rs on NK cells. (2) TGF-β and IL-10 repress IL-2 and IFN-γ production and downregulate NKG2D expression. (3) IL-15 is used by RS cells for proliferation and survival, diminishing available IL-15 in TME for NK cells. (4) Upregulation of CXCL9 and CXCL10 on RS cells attracts CXCR3-expressing CD56bright–CD16dim NK cells, with lower efficacy in RS killing. (5) Interactions of MHC class I molecules, HLA-G, and HLA-E with corresponding inhibitory receptors suppress NK cell activity. (6) sMICA and sBAG6/BAT3 lead to NKG2D and NKp30 downregulation, respectively. (7) A physical barrier (“Rosetting”) consisting of Th2 T-helper cells, regulatory T cells, and macrophages shields RS cells from NK cells. (8) RS cells avoid Fas-mediated apoptosis by overexpressing c-FLIP. Expression of FasL on RS cells leads to apoptosis of Fas-expressing NK cells. (9) Interaction of PD-L1 with the cognate receptor PD-1 inhibits NK cell activation. Ligands in cHL for immune checkpoints TIGIT, TIM-3, and LAG-3 remain to be explored. Abbreviations: c-FLIP, cellular FLICE-inhibitory protein; cHL, classic Hodgkin Lymphoma; FasL, Fas ligand; IFN-γ, interferon-γ; IL, interleukin; IL-2R, IL-2 receptors; ILT, Immunoglobulin-like transcript; KIRs, Killer cell immunoglobulin-like receptor; LAG-3, lymphocyte-activation-gene-3; NK, natural killer; PD-1, Programmed cell death protein-1; PD-L1, Programmed death-ligand 1; RS, Reed–Sternberg; s, soluble; TGF-β, Transforming Growth Factor-β; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TIM-3, T-cell immunoglobulin and mucin-3.