Antitumor activity of liver natural killer (NK) cells decreases after partial hepatectomy or liver transplantation (LT), suggesting the susceptibility of patients with depressed immune status to hepatocellular carcinoma (HCC) recurrence. However, molecular mechanisms underlying decreased activity of liver NK cells remain unclear.

After 70% of hepatectomy, an intraportal (i.p.) injection of 1 × 106 Hepa1-6 hepatoma cells to B6 mice caused metastases. The expression of CD69 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on liver NK cells was temporarily down-regulated after partial hepatectomy (7 mice experiments; p<0.01 for day three vs control). Adoptive transfer of TRAIL-expressing liver NK cells extracted from poly I:C-stimulated B6 mice prevented the spread of metastases in B6 or B6-Balb/c F1 mice that had undergone hepatectomy and had received Hepa1-6 cells. Thus, adoptive immunotherapy using activated NK cells extracted from normal liver perfusate is a novel technique to reconstitute the depressed immune status of HCC patients receiving partial liver grafts.

To clarify the mechanism by which TRAIL expression of liver NK cells decreased after hepatectomy, we comprehensively analyzed the changes in the expression of many cytokines, chemokines, and their corresponding receptors on NK cells. After partial hepatectomy, CXCL9 mRNA levels significantly diminished in hepatic tissue (n = 7, p = 0.017), and CXCL9 protein production markedly decreased. In contrast, TRAIL-positive NK cells strongly expressed CXCR3 (98.8 ± 0.1 %), a receptor of CXCL9, compared with TRAIL-negative NK cells (20.4 ± 2.3 %), (n = 5, p = 0.008).

Thus, the significant reduction in TRAIL-expressing NK cells in remnant liver after partial hepatectomy is strongly associated with the impaired intrahepatic CXCL9–CXCR3 pathway. Our results suggest the possibility of developing strategies to augment CXCL9 concentration in the liver to prevent HCC recurrence after LT, i.e., the combination of immunotherapy using TRAIL-expressing NK cells and i.p. injection of recombinant CXCL9.

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