Recently, a review article discussing the therapeutic potential of natural killer (NK) cell biology was published in the journal Frontiers of Medicine. The article is titled "Intracellular checkpoints for NK cell cancer immunotherapy".
NK cells play a key role in the innate immune response against cancer and viral infection, and their presence in tumors is associated with the prognosis of patients with various cancers. However, due to imbalanced immunoregulatory signals, NK cells in the tumor microenvironment are often functionally exhausted, manifested as reduced numbers and impaired function. This exhaustion is affected by immune checkpoint receptors, which are inhibitory cell surface receptors that inhibit anti-tumor immune responses.
Figure 1. Intracellular checkpoint molecules from different aspects of NK cell biology. (Huang Y, Tian Z, Bi J., 2024)
Notably, immune checkpoint molecules within NK cells, such as FBP-1, EZH2, CIS, TIPE2, and HIF-1α, play an important role in NK cell exhaustion by affecting NK cell metabolism, proliferation, survival, and cytotoxicity. These molecules provide a universal target for cancer immunotherapy because their effects on anti-tumor immune responses are consistent in different contexts.
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The intricate relationship between NK cells and cancer is further complicated by the expression of HLA class I molecules, which interact with inhibitory KIR on the surface of NK cells and regulate NK cell activity. The polymorphism of KIR and its ligands adds a layer of complexity to the interaction between NK cells and tumor cells. In addition, other inhibitory receptors, such as CD94/NKG2A, PD-1, TIGIT, and TIM-3, are often expressed in tumor tissues and can serve as background detection molecules to influence antitumor immune responses based on the presence and level of their ligands.
Intracellular immune checkpoint molecules, such as BIM, which mediates NK cell apoptosis, can be targeted to enhance antitumor responses. It has been shown that the loss of BIM in NK cells increases their resistance to apoptosis and accumulation in late maturation, potentially enhancing their antitumor ability. Similarly, the E3 ubiquitin protein ligase Cbl-b negatively regulates the cytolytic activity of NK cells, and its inhibition can improve NK cell-mediated control of tumor metastasis.
CIS is a negative regulator of IL-15 signaling that is upregulated by IL-15 in NK cells. Its loss enhances NK cell sensitivity to IL-15, proliferation, survival, and cytotoxicity against tumor cells. EZH2 is a component of the polycomb inhibitory complex 2 and a negative regulator of NK cell effector function. Targeting it may promote NK cell immunotherapy. FBP1 is a glucose-producing enzyme that inhibits glycolysis in NK cells. Its inhibition restores NK cell activity, suggesting a role in NK cell exhaustion.
TIPE2 is a negative regulator of IL-15 signaling, which is upregulated in multiple contexts and inhibits downstream activation of AKT and Ral. Loss of TIPE2 in NK cells results in enhanced functional maturation, cytotoxicity, and IFN-γ production, suggesting its potential as an immune checkpoint for the development of NK cell immunotherapy. HIF-1α is a transcription factor involved in the cellular response to hypoxia that negatively regulates IL-18-driven NF-κB signaling and the antitumor activity of tumor-infiltrating NK cells. Inhibition of HIF-1α in NK cells may improve solid tumor therapy.
Compared with targeting immune checkpoint receptors on the cell surface, targeting checkpoint molecules within NK cells has a more universal therapeutic potential. This is because the efficacy of the latter is often tumor-specific and dependent on ligand interactions. Targeting intracellular checkpoints can be combined with other strategies, such as tumor sensor proteins, immune checkpoint blockade, and synthetic gene circuits, to enhance NK cell immunotherapy. Emerging intracellular checkpoint molecules provide new targets for improving the antitumor activity of NK cells. Understanding their mechanisms of action is essential to identify targetable checkpoints.
Strategies targeting intracellular checkpoint molecules include CRISPR/Cas9, shRNA, and small molecule inhibitors, each with its own challenges and limitations. Developing NK cell gene editing technologies and improving viral transfection platforms are essential to achieve stable gene overexpression in NK cells. Discovering and targeting these intracellular checkpoints is expected to improve the efficacy of NK cell immunotherapy in cancer treatment.
Reference
Huang Y, Tian Z, Bi J. Intracellular checkpoints for NK cell cancer immunotherapy. Frontiers of Medicine, 2024: 1-15.