Abstract
Liver transplantation for hepatocellular carcinoma (HCC) results in a specific condition where the immune response is potentially directed against both allogeneic and cancer antigens. We have investigated the level of anti-cancer immunity during allogeneic immune response. Dark Agouti-to-Lewis and Lewis-to-Lewis rat liver transplantations were performed and the recipients anti-cancer immunity was analysed at the time of alloimmune activation. The occurrence of rejection in the allogeneic recipients was confirmed by a shorter survival (p<0.01), increased liver function tests (p<0.01), the presence of signs of rejection on histology, and a donor-specific ex vivo mixed lymphocyte reaction. At the time of alloimmune activation, blood mononuclear cells of the allogeneic group demonstrated increased anti-cancer cytotoxicity (p<0.005), which was related to an increased natural killer (NK) cell frequency (p<0.05) and a higher monocyte/macrophage activation level (p<0.01). Similarly, liver NK cell anti-cancer cytotoxicity (p<0.005), and liver monocyte/macrophage activation levels (p<0.01) were also increased. The alloimmune-associated cytotoxicity was mediated through the NKG2D receptor, whose expression was increased in the rejected graft (p<0.05) and on NK cells and monocyte/macrophages. NKG2D ligands were expressed on rat HCC cells, and its inhibition prevented the alloimmune-associated cytotoxicity. Although waiting for in vivo validation, alloimmune-associated cytotoxicity after rat liver transplantation appears to be linked to increased frequencies and levels of activation of NK cells and monocyte/macrophages, and is at least in part mediated through the NKG2D receptor.
Highlights
Liver transplantation is the most effective treatment for patients with early unresectable hepatocellular carcinoma (HCC) [1,2]
This study provides novel insights to the question of the balanced immune activation after allogeneic liver transplantation in the presence of HCC, by demonstrating the presence of an alloimmune-dependent anti-cancer cytotoxic activity after rat liver transplantation
This cytotoxicity is linked to increased frequencies and levels of activation of natural killer (NK) cells and monocyte/macrophages, and is at least in part mediated through the NKG2D receptor
Summary
Liver transplantation is the most effective treatment for patients with early unresectable hepatocellular carcinoma (HCC) [1,2]. Various strategies have been proposed to decrease this risk, including an improved transplant selection criteria, the targeting of circulating HCC cells, the use of adjuvant anti-cancer drugs and a promoted anti-cancer immunity [4]. Transplantation for HCC is a unique condition, with immune activation directed against both allogeneic donor and cancer antigens This dual activation has rarely been explored. An alloimmune activation may only be directed against specific allogeneic antigens or be linked to a broader activation promoting a non-specific anti-cancer immune response The latter hypothesis has been suggested by a number of studies showing a higher risk of post-transplant HCC recurrence in patients with more profound immune inhibition; for example, after the use of anti-lymphocyte antibodies or in case of overexposure to calcineurin inhibitors [5,6,7,8]. A decreased expression of one NKG2D ligand on HCC tumors, low neutrophillymphocyte blood ratios and tumor-associated macrophage counts have been associated with HCC recurrence [9,10,11,12]
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