November 28, 2024
National Cancer Center Japan
Keio University School of Medicine
Key Points
We have succeeded in developing the world's first mouse model that spontaneously develops NK cell lymphoma and can reproduce its immune environment. This mouse develops tumors in characteristic organs such as the salivary glands and exhibits a pathology similar to extranodal NK/T-cell lymphoma, nasal type (ENKTCL), an intractable disease that occurs frequently in Asia.
We discovered that the cell of origin for both this mouse model and human NK cell lymphoma is the tissue-resident NK cell. This finding will help elucidate the pathogenic mechanism of ENKTCL.
The mechanism of involvement of the Epstein-Barr virus (EBV), a type of herpesvirus, in ENKTCL, which was previously unclear, has been clarified.
This study has paved the way for the development of new therapies by demonstrating that targeting proteins specifically expressed in the tumors of the mouse model or signaling pathways of immune cells activated within the tumor extends survival in the mouse model.
A research group led by Visiting Researcher Atsushi Furuya (Senior Lecturer, Division of Hematology, Department of Internal Medicine, Keio University School of Medicine) and Division Chief Keisuke Kataoka (Professor, Division of Hematology, Department of Internal Medicine, Keio University School of Medicine) of the Division of Molecular Oncology at the National Cancer Center Research Institute (Director: Hiroyuki Mano), National Cancer Center Japan (President: Hitoshi Nakagama, Chuo-ku, Tokyo), has developed a novel mouse model of NK (natural killer) cell lymphoma and elucidated its pathogenic mechanism.
In this study, by specifically deleting the tumor suppressor gene Trp53 in NK cells, we succeeded for the first time in the world in developing a mouse model that spontaneously develops NK cell lymphoma in the hematopoietic system and salivary glands, making it possible to properly evaluate the tumor immune microenvironment.
Analysis of this model revealed the following three points. First, in the salivary glands, which are rich in tissue-resident NK cells that perform immune functions without circulating throughout the body like typical lymphocytes, an increase in immature NK cells was observed even before tumor onset. This finding suggests that tissue-resident NK cells may be the origin of this tumor, and similar characteristics were confirmed in human extranodal NK/T-cell lymphoma, nasal type (ENKTCL).
Second, we elucidated that the expression of the EBV-derived protein LMP1 alters the tumor immune microenvironment, specifically promoting the proliferation of dendritic cells, and accelerates tumor development.
Third, we confirmed that a protein called KLRG1, which is specifically expressed in the tumor cells of this mouse model, is also expressed in human ENKTCL cells. Furthermore, we demonstrated that treatment targeting KLRG1 resulted in a survival-extending effect.
The mouse model developed in this study is the first model that allows for the evaluation of interactions within the tumor immune microenvironment. This achievement not only contributes to elucidating the pathogenic mechanism of the intractable disease ENKTCL but also provides important clues for the development of new therapies.
The results of this research were published in the British scientific journal " Nature Communications " on October 22, 2024 (U.S. Eastern Time).
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