ARID1A mutation drives gastric tumorigenesis via activating type 2 immune dominant microenvironment
<i>ARID1A</i> is a frequently mutated gene in gastric cancers (GCs), particularly in those associated with the Epstein-Barr virus (EBV), which also often shows <i>PIK3CA</i> mutations and <i>CDKN2A</i> silencing. However, the role of these alterations in the development of GC remains unclear. Here, using <i>Tff1</i>Cre; <i>Arid1a</i> <sup>flox/flox</sup>; <i>Cdkn2a (p16)</i> <sup>flox/flox</sup>; LSL-<i>Pik3ca</i> <sup><i>H1047R</i></sup> mice (APP mice), we found that <i>Arid1a</i> 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. <i>Arid1a</i> and <i>Pik3ca</i> 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 <i>ARID1A</i> mutations. In conclusion, type 2 immune microenvironment is a hallmark of <i>ARID1A</i>-mutated GCs and represents a promising therapeutic target.
Authors
- Keisuke Yamamoto (ORCID: https://orcid.org/0000-0002-6323-9540)
- Hiroto Kinoshita (ORCID: https://orcid.org/0000-0002-8179-6017)
- Tetsuo Ushiku (ORCID: https://orcid.org/0000-0002-1763-8380)
- Sozaburo Ihara (ORCID: https://orcid.org/0000-0001-8495-2073)
- Hideaki Ijichi (ORCID: https://orcid.org/0000-0002-2379-7986)
- Sohei Abe
- Junya Arai (ORCID: https://orcid.org/0000-0002-4905-7046)
- Nobumi Suzuki (ORCID: https://orcid.org/0000-0001-9566-8828)
- Masahiro Hata (ORCID: https://orcid.org/0000-0002-3836-3515)
- Yuki Matsushita (ORCID: https://orcid.org/0000-0001-9577-3249)
- Satoshi Kawamura (ORCID: https://orcid.org/0000-0003-3140-8255)
- Gloria H. Su (ORCID: https://orcid.org/0000-0002-5158-6019)
- Mitsuhiro Fujishiro (ORCID: https://orcid.org/0000-0002-4074-1140)
- Yoshihiro Hirata (ORCID: https://orcid.org/0000-0002-8324-366X)
- Tsuneo Ikenoue (ORCID: https://orcid.org/0000-0001-8264-2573)
- Chie Uekura
- Yoku Hayakawa (ORCID: https://orcid.org/0000-0002-3988-2499)
- Hayato Nakagawa (ORCID: https://orcid.org/0000-0002-6973-5094)
- Hiroaki Fujiwara (ORCID: https://orcid.org/0000-0003-0519-2796)
- Hiroaki Tateno (ORCID: https://orcid.org/0000-0003-3006-1659)
- Chihiro Shiomi
- Timothy C. Wang (ORCID: https://orcid.org/0000-0001-5730-3019)
- Yusuke Iwata (ORCID: https://orcid.org/0000-0002-4125-132X)
- Ken Kurokawa (ORCID: https://orcid.org/0000-0001-8389-3315)
- T. Shiokawa
- Masato Kasuga
- Mayo Tsuboi
- K. Murakami
- Yukiko Oya
Institutions
- Mie University (JP)
- The Institute of Medical Science, Asahi Life Foundation (JP)
- Tokyo Medical University Hospital (JP)
- University of Tokyo Hospital (JP)
- Center for Digestive and Liver Diseases (US)
- National Institute of Advanced Industrial Science and Technology (JP)
- The University of Tokyo (JP)
- Columbia University (US)
Publication Details
- Journal
- iScience
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1016/j.isci.2025.113117
- Citations
- 2
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science