NK cells are an important type of innate immune lymphocytes, mainly distributed in peripheral blood and lymphoid tissues. This type of cell can recognize and kill tumor cells and virus-infected cells without pre-sensitization, playing a key role in immune surveillance. First discovered by Kiessling and Herberman in 1975, NK cells are named for their "natural killing" property. Its surface expresses a variety of activating and inhibitory receptors, precisely regulating cytotoxic functions by dynamically balancing these signals. The unique killing mechanism of NK cells (such as the release of perforin and granzyme) provides new ideas for cancer immunotherapy. Currently, NK cell-based therapies have become an important research direction in tumor biological treatment.
NK cells, as the core effector cells of the innate immune system, rely on the synergistic effect of multiple characteristic receptor molecules on their surface for their function: the killer cell immunoglobulin-like receptor (KIR) family specifically recognizes MHC class I molecules through 2-3 immunoglobulin-like domains. C-type lectin-like receptors (such as NKG2D) utilize carbohydrate recognition domains to bind stress-induced ligands; Natural cytotoxic receptors (such as NKp46) directly participate in target cell recognition through the immunoglobulin superfamily domain, and these receptors together form a precise recognition and regulatory network.
Fig. 1 NK cell cytolytic activation.1
Key structural properties of NK cell:
The core function of NK cells is to mediate the immune surveillance and killing of abnormal cells, and they are also involved in various immune regulatory processes.
| Function | Description |
| Cytotoxic killing | Direct killing of tumor cells and virus-infected cells by the release of perforin and granzyme is the first line of defense of innate immunity. |
| Antibody-dependent cytotoxicity (ADCC) | FcγRIIIa (CD16) was used to recognize the target cells coated with antibodies and enhance the specific killing effect. |
| Immune regulation | Secrete cytokines such as IFN-γ and TNF-α to regulate the immune responses of T cells and macrophages. |
| Regulation of graft-versus-host disease (GVHD) | Balance the leukemia effect of grafts and the risk of GVHD after hematopoietic stem cell transplantation. |
| Maintenance of tissue homeostasis | By eliminating senescent and damaged cells, it participates in tissue repair and homeostasis regulation. |
The activation of NK cells follows a "missing self" recognition pattern. Inhibitory receptors (such as KIR) bind to MHC Class I molecules to inhibit the killing function, while activating receptors (such as NKG2D) recognize stress ligands to trigger cytotoxicity. This dual regulatory mechanism ensures the precise identification of abnormal cells.
1. Murin, Charles D. "Considerations of antibody geometric constraints on NK cell antibody dependent cellular cytotoxicity." Frontiers in Immunology 11 (2020): 1635. https://doi.org/10.3389/fimmu.2020.01635
This article reviews the molecular mechanisms of the interaction between antibody characteristics (such as subtypes and glycosylation) and FcγRIIIa receptors in antibody-dependent cytotoxicity (ADCC) of NK cells, explores the influence of spatial geometric features of immune synapses on activation signals, and looks forward to the promoting effect of high-throughput technology on the development of NK cell therapeutic drugs.
2. Wang, Wei, et al. "NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy." Frontiers in immunology 6 (2015): 368. https://doi.org/10.3389/fimmu.2015.00368
This article demonstrates that myoglobin plays a central role in rhabdomyolysis- and crush syndrome-associated acute kidney injury (RM/CS-AKI), and highlights the potential of a high-affinity anti-myoglobin rabbit monoclonal antibody (RabMAb) as an effective emergency treatment that blocks myoglobin-induced kidney toxicity.
3. Seidel, Ursula JE, Patrick Schlegel, and Peter Lang. "Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies." Frontiers in immunology 4 (2013): 76. https://doi.org/10.3389/fimmu.2013.00076
The article indicates that over the past decade, multiple therapeutic antibodies approved by the FDA/EMA have relied on NK cell-mediated ADCC effects. The mismatch between the FcγRIIIa-V158F polymorphism and the KIR ligand affects the clinical efficacy, and antibody engineering modification is further enhancing the activity of ADCC. This article reviews the relevant mechanisms and therapeutic applications.
4. Campbell, Kerry S., Adam D. Cohen, and Tatiana Pazina. "Mechanisms of NK cell activation and clinical activity of the therapeutic SLAMF7 antibody, elotuzumab in multiple myeloma." Frontiers in immunology 9 (2018): 2551. https://doi.org/10.3389/fimmu.2018.02551
The article indicates that elotuzumab, a monoclonal antibody targeting SLAMF7, activates NK cells through a dual mechanism: the CD16-mediated ADCC effect and the synergistic stimulation of the SLAMF7-EAT-2 signaling pathway enhance the immunotherapy for multiple myeloma and produce a synergistic effect with drugs such as lenalidomide.
5. Khan, Muhammad, Sumbal Arooj, and Hua Wang. "NK cell-based immune checkpoint inhibition." Frontiers in immunology 11 (2020): 167. https://doi.org/10.3389/fimmu.2020.00167
The article indicates that NK cell immune checkpoint therapy has become a new direction in cancer treatment. Besides the classic KIRs/NKG2A, new targets such as PD-1, TIGIT, and Siglec-7/9 have emerged one after another. The dual-checkpoint blockade and combined ADCC enhancement strategy can synergistically improve the anti-tumor efficacy.
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