Endogenous immune regulatory pathways controlling NK and NKT cell activity in the tumor microenvironment

The endogenous immune regulatory pathways controlling NK and NKT cell activity represent a complex network of inhibitory and activating signals that dictate the magnitude of the innate and bridge-to-adaptive immune response against malignancies (Vivier et al., 2018, Nature). In the tumor microenvironment (TME), these pathways are often skewed toward immunosuppression through the upregulation of checkpoint receptors such as NKG2A, TIGIT, and PD-1 on NK/NKT cells, and the expression of their corresponding ligands (e.g., HLA-E, PVR, PD-L1) on tumor cells (André et al., 2018, Cell). Additionally, soluble factors like TGF-beta and adenosine, along with metabolic stressors like hypoxia, further dampen NK cell cytotoxicity and cytokine production (Wolf et al., 2023, Frontiers in Immunology). Therapeutic strategies targeting these pathways aim to 'release the brakes' on NK cells using monoclonal antibodies like monalizumab (anti-NKG2A) or tiragolumab (anti-TIGIT), or to provide 'gas' through cytokine mimetics like N-803 (IL-15 superagonist) (ClinicalTrials.gov). These approaches are currently being evaluated in various clinical trials, often in combination with T-cell-directed therapies, to overcome tumor-induced immune evasion. However, the heterogeneity of the TME and the redundancy of inhibitory signals present significant challenges for achieving durable clinical responses.

Other names

NK cell checkpointsNKT cell regulatory networkInnate immune checkpointsTumor-induced NK cell exhaustion pathwaysNK cell activating and inhibitory signaling

Modulation of inhibitory and activating receptors on NK and NKT cells to restore anti-tumor effector functions and overcome immune evasion.