NK cell exhaustion in the tumor microenvironment

Abstract

Natural killer (NK) cells kill mutant cells through death receptors and cytotoxic granules, playing an essential role in controlling cancer progression. However, in the tumor microenvironment (TME), NK cells frequently exhibit an exhausted status, which impairs their immunosurveillance function and contributes to tumor immune evasion. Emerging studies are ongoing to reveal the properties and mechanisms of NK cell exhaustion in the TME. In this review, we will briefly introduce the maturation, localization, homeostasis, and cytotoxicity of NK cells. We will then summarize the current understanding of the main mechanisms underlying NK cell exhaustion in the TME in four aspects: dysregulation of inhibitory and activating signaling, tumor cell-derived factors, immunosuppressive cells, and metabolism and exhaustion. We will also discuss the therapeutic approaches currently being developed to reverse NK cell exhaustion and enhance NK cell cytotoxicity in the TME.

Dual Targeting of Glioblastoma Cells with Bispecific Killer Cell Engagers Directed to EGFR and ErbB2 (HER2) Facilitates Effective Elimination by NKG2D-CAR-Engineered NK Cells

“…Furthermore, IL-15 can upregulate NKG2D expression [54], which may increase the additional recruitment of endogenous NK and CD8 + T cells by bispecific NKAB antibodies. An analysis of tumor organoid models complemented with primary immune cells and in vivo experiments in immunocompetent mouse tumor models may be helpful to further investigate the modulation of the tumor immune microenvironment by NKAR_RD-IL15-NK-92 cells and potential exhaustion of the CAR-NK cells in a setting that more closely reflects the clinical situation [55].…”

Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges

“…The exhaustion of NK cells is mainly presented by several exhaustion phenotypes such as reduction in NK cell proliferation, activation, and cytotoxicity, downregulation of cytokines and activating receptors of NK cells, upregulation of immune checkpoints and inhibitory signals on NK cells, and dysregulation in NK cell metabolism ( 62 ). For instance, the upregulation of inhibitory receptors such as PD-1, TIGIT, TIM-3 on NK cells and increase in tumor-derived factors including prostaglandin E2 (PGE2), TGF-β, adenosine, and exosomes can eventually cause NK cell inhibition and exhaustion ( 62 ). Moreover, nutrient deprivation due to reduction in oxidative phosphorylation (OXPHOS) and glycolysis on NK cells can lead to NK cell exhaustion and cytotoxicity inhibition ( 63 , 64 ).…”

“…NK cell exhaustion can be reduced by targeting inhibitory signals induced by KIRs, PD-1, TIGIT, NKG2A, and TIM-3 of NK cells ( 62 , 119 ). Moreover, various alkylating agents, proteasome inhibitors, histone deacetylation inhibitors, hyperploidy-inducing agents, and glycogen synthetase kinase-3 can be implemented to upregulate the activating receptor, NKG2D on NK cells ( 120 ).…”

Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions

“…Typically, NK cells have a short lifespan and a rapid turnover rate in vivo, which are natural characteristics that distinguish them from longer-lived lymphocytes like T cells [ 17 ]. In the tumor setting, the harsh conditions of the microenvironment, including hypoxia, nutrient deprivation, and exposure to immunosuppressive factors such as prostaglandin E2 (PGE2) and adenosine, further exacerbate the challenge by promoting NK cell apoptosis and dysfunction [ 63 ]. Moreover, the activation and cytotoxicity of NK cells are tightly regulated by a balance of activating and inhibitory signals.…”