Arai Junya, Hayakawa Yoku, Suzuki Nobumi, Kinoshita Hiroto, Hata Masahiro, Kurokawa Ken, Matsushita Yuki, Abe Sohei, Oya Yukiko, Tsuboi Mayo, Ihara Sozaburo, Iwata Yusuke, Murakami Keita, Shiokawa Toshiro, Shiomi Chihiro, Uekura Chie, Yamamoto Keisuke, Fujiwara Hiroaki, Kawamura Satoshi, Nakagawa Hayato, Ikenoue Tsuneo, Tateno Hiroaki, Ushiku Tetsuo, Ijichi Hideaki, Hirata Yoshihiro, Kasuga Masato, Su Gloria H, Wang Timothy C, Fujishiro Mitsuhiro
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Division of Gastroenterology, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan.
iScience. 2025 Jul 15;28(8):113117. doi: 10.1016/j.isci.2025.113117. eCollection 2025 Aug 15.
is a frequently mutated gene in gastric cancers (GCs), particularly in those associated with the Epstein-Barr virus (EBV), which also often shows mutations and silencing. However, the role of these alterations in the development of GC remains unclear. Here, using Cre; ; ; LSL- mice (APP mice), we found that deletion alone promoted a type 2 immune microenvironment marked by the infiltration of type 2 innate lymphoid cells (ILC2s), eosinophils, mast cells, and M2 macrophages via triggering aberrant IL-33-expressing pit lineage differentiation in stem/progenitor cells. Targeting interleukin (IL)-33, IL-13, and ILC2 activation suppressed metaplasia and tumor progression in APP mice. and mutations cooperatively promoted cell proliferation through v-Akt murine thymoma viral oncogene homolog (AKT) phosphorylation at distinct sites. This type 2 immune response was also observed in human GC samples harboring EBV or mutations. In conclusion, type 2 immune microenvironment is a hallmark of -mutated GCs and represents a promising therapeutic target.
是胃癌（GCs）中一种常见的突变基因，尤其是在与爱泼斯坦-巴尔病毒（EBV）相关的胃癌中，EBV也常出现突变和沉默。然而，这些改变在GC发生发展中的作用仍不清楚。在此，我们使用Cre; ; ; LSL- 小鼠（APP小鼠）发现，单独缺失 通过触发干/祖细胞中异常表达IL-33的胃小凹谱系分化，促进了以2型固有淋巴细胞（ILC2s）、嗜酸性粒细胞、肥大细胞和M2巨噬细胞浸润为特征的2型免疫微环境。靶向白细胞介素（IL）-33、IL-13和ILC2激活可抑制APP小鼠的化生和肿瘤进展。 和 突变通过在不同位点的v-Akt小鼠胸腺瘤病毒癌基因同源物（AKT）磷酸化协同促进细胞增殖。在携带EBV或 突变的人GC样本中也观察到了这种2型免疫反应。总之，2型免疫微环境是 -突变GCs的一个标志，代表了一个有前景的治疗靶点。
