In a study published in Nature Immunology on January 31, Prof. MENG Guangxun from the Shanghai Institute of Immunity and Infection (SIII) of the Chinese Academy of Sciences, and Prof. LIU Chen-Ying from Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, unveiled a novel mechanism whereby a short form of IL-18, generated by caspase-3 cleavage in tumor cells, activates NK cells to suppress tumor growth, offering new therapeutic opportunities.
While immunotherapy, including CAR-T cell therapy, has made significant advances, the response rates in treating various solid tumors remain suboptimal, underlining the urgent need for understanding tumor evading mechanisms and innovative treatment strategies. CD8+T cells and NK cells are the main immune cells conducting immune clearance of tumors. As a key component of the innate immune system, NK cells are increasingly recognized for their potential in cancer immunotherapy due to their rapid response, broad anti-tumor activity, and minimal toxicity. However, tumors employ various mechanisms to evade immune surveillance, such as reducing the expression of key immune modulators including IL-18.
In this study, the researchers focused on IL-18, which is produced as an inactive precursor (pro-IL-18) and requires cleavage by caspase-1 to become the mature, active form. The mature IL-18 is secreted from immune cells such as macrophage, and activates immune cells for tumor control through IL-18 receptor-mediated signal. However, this process is often compromised by a decoy receptor IL-18 binding protein (IL-18BP). In the current work, Prof. MENG’s team discovered that tumor cells can produce a novel short form of IL-18 via caspase-3 cleavage, which is independent of traditional mature IL-18 pathway. Unlike mature IL-18, this short form does not exit the cell but enter the nucleus, where it promotes the phosphorylation of STAT1 and ISG15 secretion, which in turn enhances NK cell anti-tumor function.
This discovery is particularly relevant in colorectal cancer, wherein the short IL-18 is negatively correlated with tumor progression in clinical samples. Intriguingly, short IL-18 promotes NK cell anti-tumor activity by modulating key signaling pathways, offering a novel and unexpected mechanism through which IL-18 can enhance immune responses in the tumor microenvironment.
“This is a groundbreaking finding that challenges our previous understanding of IL-18,” said Prof. MENG. “By identifying the role of short IL-18 in activating NK cells, we open up new possibilities for developing targeted immunotherapies that may complement existing treatments.”
This study significantly advances our understanding of IL-18’s role in cancer immunotherapy. By inducing short IL-18 expression in tumor cells, the researchers suggest that new therapeutic strategies can be developed to enhance the efficacy of NK cell-based immunotherapies. With further mechanistic studies and clinical validation, these findings may provide a novel therapeutic avenue for cancer patients.
Figure. Schematic model summarizing the anti-tumor mechanisms of mature IL-18 and short IL-18, created by Figdraw. (Image by SIII)
Reference: https://www.nature.com/articles/s41590-024-02074-7
