A trainer: IL-18 enhances the battle effectiveness of NK cells against cancer cells
2024-01-30
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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]
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]
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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- Yasuda K, Nakanishi K, Tsutsui H. Interleukin-18 in Health and Disease. Int J Mol Sci. 2019 Feb 2;20(3):649.
- 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.
- Vogler M, Shanmugalingam S, Särchen V, Reindl LM, Grèze V, Buchinger L, Kühn M, Ullrich E. Unleashing the power of NK cells in anticancer immunotherapy. J Mol Med (Berl). 2022 Mar;100(3):337-349.
- Senju H, Kumagai A, Nakamura Y, Yamaguchi H, Nakatomi K, Fukami S, Shiraishi K, Harada Y, Nakamura M, Okamura H, Tanaka Y, Mukae H. Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy. Int J Biol Sci. 2018 Mar 9;14(3):331-340.
- Senju H, Kumagai A, Nakamura Y, Yamaguchi H, Nakatomi K, Fukami S, Shiraishi K, Harada Y, Nakamura M, Okamura H, Tanaka Y, Mukae H. Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy. Int J Biol Sci. 2018 Mar 9;14(3):331-340.
- Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57–63.
- Tomura M, Zhou XY, Maruo S, Ahn HJ, Hamaoka T, Okamura H, Nakanishi K, Tanimoto T, Kurimoto M, Fujiwara H. A critical role for IL-18 in the proliferation and activation of NK1.1+ CD3- cells. J Immunol. 1998 May 15;160(10):4738-46.
- Tarannum M, Romee R. Cytokine-induced memory-like natural killer cells for cancer immunotherapy. Stem Cell Res Ther. 2021 Dec 4;12(1):592.
- Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA. Cytokine activation induces human memory-like NK cells. Blood. 2012 Dec 6;120(24):4751-60.
- Islam R, Pupovac A, Evtimov V, Boyd N, Shu R, Boyd R, Trounson A. Enhancing a Natural Killer: Modification of NK Cells for Cancer Immunotherapy. Cells. 2021 Apr 29;10(5):1058.