Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the fourth leading cause of cancer-related deaths worldwide. Although therapeutic options have improved in the last few years, mortality remains disturbingly high. The key role of innate immunity, particularly of natural killer (NK) cells, in tumor surveillance and response is well established. The anti-tumor NK cell activity is modulated by interactions between NK cells activating or inhibiting receptors and their ligands, expressed or released by tumor cells. Alterations in these networks lead to inadequate NK cell responses and a lack of cancer control. In our study, we focus on NK cells activating receptor DNAM-1 and its ligand CD155, expressed in HCC cells. We provide evidence of impaired NK cytotoxic function as a result of altered receptor/ligand axis. We conclude that this may represent a tumor escape mechanism and a possible target for new immunotherapeutic approaches to HCC treatment. ABSTRACT: Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. Methods: Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. Results: sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. Conclusions: We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance.