Table 1.
NK cell evasion mechanisms in cHL.
| Mechanism | Source | Description |
|---|---|---|
| Soluble CD25 | RS cells | Prevent interaction of IL-2 with IL-2Rs |
| IL-10 | RS cells, Tregs, cells of TME | Repress IL-2 and IFN-γ production |
| TGF-β | RS cells, Tregs, cells of TME | Repress IL-2 and IFN-γ productionDownregulate activating receptors (NKG2D, NKp30) and corresponding ligands (MICA, ULBP2, ULBP4) |
| IL-15 | RS cells | Competition of RS cells and NK cells |
| CXCL9, CXCL10 | RS cells (mainly EBV+) | Attract CD56bright–CD16dim NK cells |
| HLA-G and HLA-E | RS cells | Bind to inhibitory receptors on NK cells |
| Soluble MICA | RS cells | Endocytosis and degradation of NKG2D |
| BAG6/BAT3 | RS cells | Endocytosis and degradation of NKp30 |
| Rosetting | Macrophages, Tregs, Th2 T-helper cells | Physical shield of HRS cells from NK cells |
| c-FLIP | Overexpressed by RS cells | NK FasL-mediated apoptosis resistance |
| FasL | RS cells | Apoptosis of Fas-expressing NK cells |
| PD-L1 | RS cells | Suppression of NK cell activation |
| MHC-I | RS cells (EBV+) | Bind to KIRs, inhibit NK cell activation |
c-FLIP, cellular FLICE-inhibitory protein; cHL, classic Hodgkin’s Lymphoma; EBV, Epstein–Barr Virus; FasL, Fas Ligand; IFN-γ, Interferon-gamma; IL, Interleukin; IL-2Rs, Interleukin-2 receptors; LAG-3, Lymphocyte-activation-gene-3; NK, Natural Killer cells; PD-1, Programmed Cell Death Protein-1; RS, Reed–Sternberg cells; TGF-β, Transforming Growth Factor-β; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; TME, Tumor Microenvironment; Tregs, regulatory T-cells.