Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

SIMPLE SUMMARY: The reciprocal crosstalk between dendritic cells (DCs) and natural killer (NK) cells plays a pivotal role in regulating immune defense against viruses and tumors. The Th-cell polarizing ability, cytokine-producing capacity, chemokine expression, and migration of DCs are regulated by activated NK cells. Conversely, the effector functions including lysis and cytokine production, proliferation, and migration of NK cells are influenced by close interactions with activated DCs. In this review, we explore the impact of DC–NK cell crosstalk and its therapeutic potential in immune control of liver malignances. ABSTRACT: Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.