Clinical and experimental medicine · 2025
The role and mechanism of ARID1A in immunotherapy of gastric cancer.
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He Wenting, Chen Yue, Yao Xue, Wu Jun, Zhu Danxia, Wang Jian, Jiang Lu, Shen Yueping, Zhang Dachuan, Jiang Jingting
Аннотация
OBJECTIVE: This study aimed to clarify the clinical significance of ARID1A expression in gastric cancer (GC) and explore its mechanistic role in regulating PD-L1 expression during immunotherapy response.
METHODS: A comprehensive analysis of ARID1A expression was conducted in 205 gastric adenocarcinoma specimens and 30 matched paracancerous tissues. ARID1A and PD-L1 expression profiles were assessed through immunohistochemical analysis. Functional studies using ARID1A-depleted GC cell lines were performed to uncover the underlying molecular mechanisms, with a particular focus on the PI3K/AKT signaling pathway.
RESULTS: ARID1A deficiency was predominantly observed in GC tissues (42.4%) compared to paracancerous tissues (13.3%, P < 0.01). This loss was significantly associated with aggressive clinicopathological features and reduced overall survival (median: 21.2 vs. 49.0 months, P < 0.001). Multivariate analysis identified ARID1A as an independent prognostic indicator. ARID1A status significantly influenced the efficacy of PD-1 inhibitors (P < 0.01), with its loss predicting an enhanced therapeutic response. Mechanistically, ARID1A depletion promoted tumor aggressiveness and increased PD-L1 expression via activation of the PI3K/AKT pathway.
CONCLUSION: Our findings demonstrate that ARID1A deficiency, while linked to poor prognosis, paradoxically enhances sensitivity to immunotherapy in GC. The newly identified ARID1A-PI3K/AKT-PD-L1 axis represents a promising therapeutic target, highlighting the potential utility of PI3K/AKT inhibitors in treating ARID1A-deficient GC.
METHODS: A comprehensive analysis of ARID1A expression was conducted in 205 gastric adenocarcinoma specimens and 30 matched paracancerous tissues. ARID1A and PD-L1 expression profiles were assessed through immunohistochemical analysis. Functional studies using ARID1A-depleted GC cell lines were performed to uncover the underlying molecular mechanisms, with a particular focus on the PI3K/AKT signaling pathway.
RESULTS: ARID1A deficiency was predominantly observed in GC tissues (42.4%) compared to paracancerous tissues (13.3%, P < 0.01). This loss was significantly associated with aggressive clinicopathological features and reduced overall survival (median: 21.2 vs. 49.0 months, P < 0.001). Multivariate analysis identified ARID1A as an independent prognostic indicator. ARID1A status significantly influenced the efficacy of PD-1 inhibitors (P < 0.01), with its loss predicting an enhanced therapeutic response. Mechanistically, ARID1A depletion promoted tumor aggressiveness and increased PD-L1 expression via activation of the PI3K/AKT pathway.
CONCLUSION: Our findings demonstrate that ARID1A deficiency, while linked to poor prognosis, paradoxically enhances sensitivity to immunotherapy in GC. The newly identified ARID1A-PI3K/AKT-PD-L1 axis represents a promising therapeutic target, highlighting the potential utility of PI3K/AKT inhibitors in treating ARID1A-deficient GC.