Figure 4.

Mechanisms Driving NK Cell Dysfunction During Cancer. Many processes that occur during cancer and cancer therapy can cause dysfunction of NK cells. The tumor microenvironment itself creates a setting full of NK cell inhibitory mechanisms. Impaired cellular metabolism increased inflammatory stimuli, hypoxia, and the localized immunosuppressive cells all can promote NK cell deactivation and impair NK cytotoxicity. Secreted molecules like cytokines, adenosine, TGF-β, prostaglandin E2 (PGE2) (5), and Indoleamine 2,3-dioxygenase (IDO) in the tumor milieu also promote NK cell downregulation, exhaustion, and apoptosis [reviewed in 138)]. Secondary effects of cancer and cancer therapy, such as depression can also affect NK cell function. Stressors can activate glucocorticoid hormone production via the hypothalamic-pituitary-adrenal axis which can induce PD-1 expression on NK cells and impairs NK cell cytotoxicity and cytokine release. Cancer therapies such as chemotherapy, radiation, and surgical resection can all cause NK cell dysfunction. Both chemotherapy and radiation have been shown to decrease NK cell population and impair NK cell cytotoxicity and IFN-γ levels. Surgical resection and perioperative factors have been shown to impair NK cell function. For example, increases in immunosuppressive cell populations such as MDSCs induce scavenger receptor expression on NK cells which promotes lipid accumulation which negatively regulates NK cell receptors and results in NK cell dysfunction.