NK Cell Exhaustion

Abstract

Natural killer cells are important effector lymphocytes of the innate immune system, playing critical roles in antitumor and anti-infection host defense. Tumor progression or chronic infections, however, usually leads to exhaustion of NK cells, thus limiting the antitumor/infection potential of NK cells. In many tumors or chronic infections, multiple mechanisms might contribute to the exhaustion of NK cells, such as dysregulated NK cell receptors signaling, as well as suppressive effects by regulatory cells or soluble factors within the microenvironment. Better understanding of the characteristics, as well as the underlying mechanisms of NK cell exhaustion, not only should increase our understanding of the basic biology of NK cells but also could reveal novel NK cell-based antitumor/infection targets. Here, we provide an overview of our current knowledge on NK cell exhaustion in tumors, and in chronic infections.

Keywords: chronic infections; immune checkpoints; immune evasion; immunotherapy; tumors.

Figure 1

Natural killer cell exhaustion. Tumor progression or chronic infections usually leads to exhaustion of NK cells. Exhausted NK cells are characterized by decreased production of effector cytokines (e.g., IFN-γ), as well as by impaired cytolytic activity. Exhausted NK cells downregulated expression of certain activating receptors and upregulated expression of inhibitory receptors. Both suppressive cells and other suppressive factors (e.g., exosomes, suppressive cytokines, hypoxia, etc.) in tumors or chronic infections might contribute to such exhausted status. Emerging strategies (e.g., immune checkpoint blockade) could potentially reverse NK cell exhaustion to boost antitumor or anti-infection immunity.