A team conducted by Jean-Pierre Couty (Team “Proliferation Stress and Liver Physiopathology” at CRC) showed that activation of the NKG2D tumor immunosurveillance system is associated with a poor prognosis in liver cancers, in contrast to other tumor types. This paradoxical effect could be due to the chronic inflammation generated by successive waves of tumor cell destruction in the liver. These results were published in Journal of Hepatology last January.
Some immune cell populations have surface receptors that can actively monitor the presence of specific ligands on other cell types. These receptor/ligand pairs form so-called immunosurveillance mechanisms that, when active and effective, recognize and destroy the ligand-expressing tumor cells. However, tumor cells have the ability to corrupt these mechanisms in order to escape these immunosurveillance systems.
Mathilde Cadoux, under the supervision of Jean-Pierre Couty, studied, in humans and mice, the immunosurveillance mechanism involving the NKG2D receptor and its ligands, MICA, MICB, and ULBP1 and 2, in the specific case of hepatocellular carcinoma or liver cancer. The NKG2D receptor, located on the surface of immune cells, is able to recognize its ligands located on the surface of tumor cells. The binding of the ligand to its receptor usually results in the destruction of the tumor cell.
Since hepatocellular carcinoma (HCC) is a serious tumor for which therapeutic options remain limited, the researchers were interested in the NKG2D immunosurveillance system in a large number of human hepatocarcinomas. In particular, they analyzed the presence of NKG2D receptor ligands on the surface of tumor cells.
Surprisingly, the results obtained indicate that the presence of the ligands MICA, MICB, and ULBP1/2, thus the activation of the immunosurveillance system, is in fact associated with a high aggressiveness of the tumors leading to a poor prognosis for the patients. Furthermore, the researchers observed that the expression of ULBP1/2 ligands is decreased in some patients that have a lower inflammatory level and a better prognosis, especially in a subgroup of human hepato-carcinomas with oncogenic activation of Wnt/beta-catenin signaling. Indeed, HCCs with activating mutations in Wnt/beta-catenin signaling (mutation in the CTNNB1 gene) have low inflammation and a better prognosis.
This work thus illustrates that in HCC, the expression of NKG2D ligands is associated with tumor aggressiveness and that, on the contrary, their decrease is indicative of a better prognosis.
The researchers repeated this type of analysis in mouse models recapitulating the main groups of human hepato-carcinomas. In this case, they observed that transcriptional expression of ULBP1/2 ligand equivalents in mice is also negatively controlled by β-catenin. In addition, expression of the NKG2D receptor (KLRK1 in mice) and the ULPB1 ligand is associated with the presence of inflammatory cells in HCCs.
Taken together, these results demonstrate that the expression of NKG2D ligands is associated with tumor aggressiveness and that their decrease by oncogenic activation of β-catenin would partly explain the low inflammatory phenotype as well as the better prognosis of this group of HCCs.
In conclusion, these results show that activation of the NKG2D immunosurveillance system is associated with a poor prognosis in liver cancers, in contrast to other tumor types. This paradoxical effect could be due to the chronic inflammation generated by successive waves of tumor cell destruction in the liver.
From a translational point of view, these results allow us to envisage in the longer term new therapeutic avenues that would target this immunosurveillance system.
Published in Journal of Hepatology on January 21, 2021 : https://www.sciencedirect.com/science/article/pii/S0168827821000283