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A trainer: IL-18 enhances the battle effectiveness of NK cells against cancer cells

2024-01-30
 
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How does IL-18 influence inflammation and immunity?

Adipocytes and macrophages are among the cell types that constitutively produce interleukin-18 (IL-18), a strong pro-inflammatory cytokine. The enzymatic cleavage of pro-IL-18, its precursor form, by caspase-1 within multi-unit complexes called inflammasomes is the process by which it is activated. For IL-18 to have its active effects, this activation stage is essential.
 
A negative feedback system governs the levels of IL-18 after secretion. In response to increased IL-18 levels, more IL-18 binding protein is synthesized with the goal of binding and inactivating IL-18 to stop unchecked proinflammatory activity and possible tissue damage.
 
The way that IL-18 affects biology is by attaching itself to a receptor complex that consists of two subunits, IL-18Rα and IL-18Rβ. The intracellular TIR signaling domains are present in both subunits. Remarkably, the receptor's β-chain intracellular signaling can only be activated by the free component of IL-18. The increase of IL-18Rα occurs when naïve T cells are stimulated with IL-12, making them more susceptible to IL-18 signaling.
 
IL-18 has a variety of downstream effects that affect immune responses. It stimulates the expression of cell adhesion molecules, increases the maturation and activation of T-cells and natural killer cells, and facilitates the synthesis of different cytokines and chemokines. Crucially, depending on the cytokine environment, IL-18's effect on CD4+ T-cells changes, inducing both Th1 and Th2 responses. It is noteworthy that this dual influence can modulate inflammatory processes. [1-3]

GMP Recombinant Protein IL18    
Activation of IL-18 and subsequent initiation of cell signaling.



How does IL-18 influence NK cells in tumor immunity?

NK cells play a crucial role in tumor immunity, recognizing and eliminating tumor cells, with their activation and expansion regulated by IL-18 through IL-18 receptors (IL-18Rs). IL-18 not only enhances NK cell expansion and cytotoxicity against tumors but also induces an APC-like phenotype, expressing CD80, CD86, HLA-DR, and HLA-DQ. This unique NK cell phenotype acts as a bridge between innate and adaptive immunity, supporting the proliferation of tumor-specific killer T cells [4], reinforcing the significance of NK cells in tumor immunity, as highlighted by the success of PD-1 immune checkpoint therapy.
 
Furthermore, IL-18 plays a pivotal role in accelerating the IL-2-induced expansion of human NK cells, offering potential improvements in immunotherapy. The synergistic effect of IL-18 with IL-2 presents a promising approach to enhance NK cell-based cancer treatments, addressing challenges in generating large numbers of therapeutic-grade NK cells. [5-7]
 
While IL-18 shares preclinical antitumor efficacy with IL-12, its clinical evaluation is limited. Nonetheless, the recognized potential of IL-18 in combination therapies, particularly in conjunction with IL-12 and IL-15 to stimulate NK cells, showcases its versatility. The cooperative effects of IL-12, IL-15, and IL-18 in generating memory-like NK cells hold promise not only for cancer immunotherapy but also for addressing various diseases, as seen in encouraging clinical trial results for relapsed/refractory acute myeloid leukemia (AML). [8-10]

GMP Recombinant Protein IL18
The NK cell-mediated tumor cell killing is coordinated by IL-2, IL-15, IL-18, and IL-21, which also activate T cells for effective tumor cell eradication.



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  2. Tsutsui H, Nakanishi K, Matsui K, Higashino K, Okamura H, Miyazawa Y, Kaneda K. IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. J Immunol. 1996 Nov 1;157(9):3967-73.
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  8. Tarannum M, Romee R. Cytokine-induced memory-like natural killer cells for cancer immunotherapy. Stem Cell Res Ther. 2021 Dec 4;12(1):592.
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