Adoptive transfer of TRAIL-expressing natural killer cells prevents recurrence of hepatocellular carcinoma after partial hepatectomy.
BACKGROUND
Antitumor activity of the liver natural killer (NK) cells reportedly decreases after partial hepatectomy, suggesting that patients with such depressed immune status are susceptible to the recurrence of hepatocellular carcinoma (HCC). We hypothesize that adoptive immunotherapy using activated NK cells can be a novel strategy to improve the depressed immune status in patients with HCC after hepatectomy or partial liver transplantation. In the present study, we have tested this hypothesis by using a mouse model.


METHODS
Intraportal injection of 1-5 x 10(6) Hepa1-6 cells (hepatoma cell line) did not result in liver metastases in untreated B6 mice, but led to the growth of liver metastases after extensive partial hepatectomy. Utilizing this murine HCC metastasis model, we investigated the antitumor activity of both remnant liver and exogenously transferred NK cells.


RESULTS
The anti-HCC activity of liver NK cells significantly decreased after partial hepatectomy. The expression of CD69 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on liver NK cells was temporarily downregulated. The adoptive transfer of NK cells, including a TRAIL-expressing fraction, extracted from the liver perfusates of poly I:C-stimulated B6 mice inhibited the growth of liver metastasis in B6 or (B6xBALB/c) F1 (B6CF1) mice that underwent hepatectomy and received intraportal Hepa1-6 injection.


CONCLUSIONS
These findings indicate that adoptive immunotherapy using activated NK cells extracted from normal liver perfusates may be a novel technique for reconstituting the depressed immune status in cases of living donor liver transplantation involving HCC patients, recipients of a partial liver graft.
Ohira
Masahiro
M
Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan.
Ohdan
Hideki
H
Mitsuta
Hiroshi
H
Ishiyama
Kohei
K
Tanaka
Yuka
Y
Igarashi
Yuka
Y
Asahara
Toshimasa
T
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006498:Hepatectomy; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology / Q000637:transplantation*; D037181:Lectins, C-Type; D008099:Liver / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis / Q000378:metabolism*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D053221:TNF-Related Apoptosis-Inducing Ligand; D000099192:CD69 Antigens