Background: Liver transplantation for hepatocellular carcinoma (HCC) results in a specific condition where the immune response is directed both against allogeneic and cancer antigens. This study assessed the level of anti-cancer immunity during allogeneic rejection after rat liver transplantation.

Methods: Dark Agouti-to-Lewis (allogeneic) and Lewis-to-Lewis (syngeneic) rat liver transplantations were performed. The occurrence of a rejection was assessed (survival, histology, liver function tests and mixed lymphocyte reaction). The phenotype, the level of activation and the anti-cancer cytotoxic activity of mononuclear, monocyte/macrophage and NK cells were tested in the peripheral blood, the liver and the spleen.

Results: Allogeneic rats experienced rejection as testified by shorter survivals (13 vs. >60 days in syngeneic rats, p<0.01), the presence of rejection on histology (Banff 8) and increased liver function tests (p<0.01). Rejection was donor specific as shown by the increased IFNΓ secretion by recipient peripheral blood mononuclear cells (day 10) after stimulation by donor splenocytes (410 pg/ml). At time of rejection, blood cells demonstrated increased anti-cancer cell cytotoxicity (25.2 vs. 14.7% in syngeneic recipients, p<0.005). This activity was related to increased blood NK cell frequencies (10.79% vs 4.9%, p<0.05) and higher blood monocyte/macrophage activation levels (p<0.01). Similarly in the liver, the number of liver mononuclear cells was increased (16.106 vs. 5.35.106 cells/liver, p<0.01), as were liver NK cell-specific cytotoxicity (58.8% vs 32% respectively, p<0.005) and liver monocyte/macrophage activation levels (p<0.01). The phenotype and the anti-cancer function of spleen cells were not altered.

Conclusion: Liver graft rejection is associated to increased peripheral and liver cytotoxicity against cancer cells. This observation supports the use of milder immunosuppression after transplantation for HCC with the idea to improve post-transplant immune clearance of HCC cells.

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