2020/09/15
University of Tsukuba
Keio University School of Medicine
Associate Professor Eishi Sugihara of the Center for Precision Medicine Development and Research at the University of Tsukuba, in a joint research project with Professor Hideyuki Saya of the Institute for Advanced Medical Research, Keio University School of Medicine, and others, has clarified the mechanism by which malignant lymphoma acquires resistance to cancer immunity.
Previously, this research group has developed various mouse models of carcinogenesis, including leukemia and osteosarcoma, by culturing mouse somatic cells *in vitro*, introducing cancer-related genes, and then transplanting them into mice. In this study, they succeeded in developing a new mouse model for lymphoma derived from well-differentiated B-cells, which had been difficult to establish using similar methods, and analyzed the process of its onset at the molecular level. The results revealed that a decrease in the expression of Fas, a cell membrane molecule that induces apoptosis (cell death), is extremely important for the onset and maintenance of lymphoma. They also found that activating CD40, a molecule involved in B-cell differentiation, in lymphoma cells restores Fas expression. On the other hand, it was found that some human lymphoma cell lines have high expression of the apoptosis inhibitor molecule Livin and exhibit resistance to apoptosis even when Fas is reactivated. Furthermore, through gene expression profile analysis, they discovered that low Fas expression and high Livin expression show a strong correlation with poor prognosis in patients with the malignant lymphomas Burkitt lymphoma and diffuse large B-cell lymphoma. Therefore, they administered an inhibitor targeting Livin to lymphoma cells with high Livin expression and confirmed, using human cell lines and mouse models, that Fas-induced apoptosis significantly increased.
From these results, it has become clear that a therapeutic strategy targeting Livin could be a very promising treatment method that enhances the effect of cancer immunity through Fas-induced apoptosis. Furthermore, Fas-induced apoptosis via the Fas ligand is one of the attack mechanisms of cytotoxic T-cells, which currently play a central role in cancer immunotherapy. This discovery is expected to lead to the elucidation of cancer immune resistance mechanisms not only in lymphoma but also in a wide range of cancer types.
The results of this research were published in the journal *Cancer Research* on September 14, 2020.
* This research was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science: Grant-in-Aid for Scientific Research (C) (#15K06840, Sugihara) and Grant-in-Aid for Challenging Exploratory Research (#15K14384, Saya, Sugihara).
For the full press release, please see below.