Abstract
Natural killer (NK)-cells are major players in the fight against viral infections and transformed cells, but there is increasing evidence attributing a disease-promoting role to NK-cells. Cytokines present in the tumor microenvironment shape NK-cell maturation, function, and effector responses. Many cytokines signal via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway that is also frequently altered and constitutively active in a broad range of tumor cells. As a consequence, there are currently major efforts to develop therapeutic strategies to target this pathway. Therefore, it is of utmost importance to understand the role and contributions of JAK–STAT molecules in NK-cell biology—only this knowledge will allow us to predict effects of JAK–STAT inhibition for NK-cell functions and to successfully apply precision medicine. We will review the current knowledge on the role of JAK–STAT signaling for NK-cell functions and discuss conditions involved in the switch from NK-cell tumor surveillance to disease promotion.
Highlights
Natural killer (NK) cells are major players of the innate immune system and immediate effector cells against viral infections, pathogens, and malignant cells
In contrast to other Janus kinase (JAK), Tyk2−/− NK-cells are present at normal numbers but show impaired IL-12/IL-18-mediated signaling with reduced STAT4 activation
The JAK–signal transducer and activator of transcription (STAT) pathway is evolutionary highly conserved; the human situation nicely matches the findings in experimental animal models
Summary
Natural killer (NK) cells are major players of the innate immune system and immediate effector cells against viral infections, pathogens, and malignant cells. NK-cells compromise 5–15% of circulating blood lymphocytes and are further sub-divided based on the expression of the cell adhesion molecule CD56 and the low affinity Fc-receptor CD16 into CD3−CD56brightCD16− and CD3−CD56dimCD16+ NK-cells. CD56bright NK-cells are mainly found in lymph nodes, produce cytokines upon activation, and possess only minor cytotoxic potential. Upon maturation to CD56dim cells—the majority of circulating NK-cells in healthy humans representing approximately 90% of NK-cells—gain significant cytotoxic potential [1, 2]. The ability of NK-cell-mediated immune surveillance extends to the prevention of metastatic spread [6,7,8], which is currently one of the dominating clinical problems in cancer therapy
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