ARID1A mutation drives gastric tumorigenesis via activating type 2 immune dominant microenvironment

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• ARID1A is frequently mutated in gastric cancers (GCs), often alongside EBV association, PIK3CA mutations, and CDKN2A silencing.
• The specific roles of these genetic alterations in GC development are not fully understood.
• Gastric cancer pathogenesis involves complex interactions between genetic mutations and the tumor immune microenvironment.

Purpose of the Study:

• To investigate the functional role of ARID1A mutations in gastric cancer development.
• To elucidate the impact of ARID1A, PIK3CA mutations, and CDKN2A silencing on the tumor immune microenvironment.
• To identify potential therapeutic targets in ARID1A-mutated gastric cancers.

Main Methods:

• Utilized a genetically engineered mouse model (APP mice) with specific gene alterations (Tff1Cre; Arid1a flox/flox; Cdkn2a (p16) flox/flox; LSL-Pik3ca H1047R).
• Analyzed the immune cell infiltration and cytokine profiles in response to Arid1a deletion.
• Investigated the cooperative effects of Arid1a and Pik3ca mutations on cell proliferation via AKT phosphorylation.
• Validated findings in human gastric cancer samples.

Main Results:

• Arid1a deletion alone induced a type 2 immune microenvironment with ILC2s, eosinophils, mast cells, and M2 macrophages.
• This was mediated by aberrant IL-33-expressing pit lineage differentiation in stem/progenitor cells.
• Targeting IL-33, IL-13, and ILC2 activation effectively suppressed metaplasia and tumor progression in mice.
• Arid1a and Pik3ca mutations synergistically enhanced cell proliferation through AKT phosphorylation.
• A similar type 2 immune response was observed in human EBV-positive or ARID1A-mutated GCs.

Conclusions:

• A type 2 immune microenvironment is a defining characteristic of ARID1A-mutated gastric cancers.
• Aberrant IL-33 signaling and type 2 immunity play critical roles in the pathogenesis of these tumors.
• Targeting the IL-33/IL-13/ILC2 axis presents a promising therapeutic strategy for ARID1A-mutated GCs.