Table 1.
Mechanisms of NK cell dysfunction in HCC.
| Mechanism | Evidence | Host | Ref. | |
|---|---|---|---|---|
| Decreased frequency and distorted subpopulations | Decreased frequency | Decline of hepatic NK cell frequency at early stage of hepatocarcinogenesis (c-myc/tgfa transgenic model) | Mouse | [31] |
| Low frequency of NK cells in intratumoral regions, compared with non-tumor liver | Human | [46,78] | ||
| Altered distributions of subpopulations | Reduction in the frequency of cytotoxic CD56dim NK population (intratumoral and peripheral) | Human | [78] | |
| Defective recognition of tumor | NKG2D downregulation | Downregulation of NKG2D on peripheral NK cells when HCC developed after HCV eradication Downregulation of NKG2D in intratumoral regions, compared with non-tumor liver |
Human | [46,80] |
| NKG2D downmodulation by soluble MICA | Association of high soluble MICA level with reduced peripheral NKG2D expression in HCC patients Shedding of MICA by ADAM17 and resultant NK cell dysfunction in a co-culture model |
Human | [82,83] | |
| Expression of NKp30 inhibitory variant | Reduced level of NCR3 immunostimulatory variants and an increased level of inhibitory variant in intratumoral and peripheral NK cells, resulting in deficient NKp30-mediated functionality | Human | [84] | |
| Defective ADCC | Association of low CD16 expression on peripheral NK cells with poor response to mAb treatment | Human | [116] | |
| Stimulation of inhibitory receptors | KIR-mediated NK inhibition | KIR-ligand mismatch prevents the generation of negative signal in allogeneic NK cell transfer | Human | [30,34] |
| KIR-HLA-mediated NK licensing (maturation) | Association of matched KIR2DL2 and HLA-C1 and delayed recurrence after RFA (HCV-HCC) Association of matched KIR-HLA types and HCC development (HBV-HCC) |
Human | [89] (HCV) [90] (HBV) |
|
| NKG2A | Expression of HLA-E, an NKG2A ligand, suggesting the possible inhibitory role of NKG2A in human HCC | Human | [128] | |
| Immunoregulatory cells and the immunosuppressive cytokines | Regulatory T cells (Treg) | Inhibits NK cells via membrane-bound and secreted TGF-β Inhibits NK cells via secreted IL-10 and TGF-β in STAT3-activated HCC |
Human Mouse |
[95,96] (Human) [97] (Mouse) |
| Myeloid-derived suppressor cells (MDSC) | Accumulation of MDSC in mice with HCC irrespective of the mouse models Inhibits NK cells via membrane bound TGF-β and the NKp30 receptor on NK cells |
Mouse Human |
[99] (Mouse) [101] (Human) |
|
| Tumor-associated macrophages (TAM) | Deviated to immunoregulatory M2 phenotype Inhibits NK cells via IL-10 and TGF-β Expresses CD48, and interacts with 2B4 on NK cells, causing NK cell dysfunction |
Human | [77,102] | |
| Immature DC | Inhibits NK cells via secretion of IL-6 and IL-10 | Human | [105] | |
| Fibroblasts | Inhibits NK cells via PGE2 and IDO | Human | [106] | |
NK, natural killer cell; HCC, hepatocellular carcinoma; NKG2D, natural killer group 2 member D; MICA/B, MHC-I polypeptide-related sequence A/B; ADAM17, a disintegrin and metalloproteases 17; NCR3, natural cytotoxicity receptor 3; ADCC, antibody-dependent cell cytotoxicity; KIR, killer cell immunoglobulin-like receptor; HLA, human leukocyte antigen; HCV, hepatitis C virus; HBV, hepatitis B virus; NKG2A, natural killer group 2 member A; TGF-β, transforming growth factor-β; PGE2, prostaglandin E2; IDO, indoleamine 2,3-dioxygenase; Ref, reference.