Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
ARID1A Loss plus CD8+ T-Cell Infiltration Associate with Favorable Clinical Outcomes in Urothelial Carcinoma.
СтатьяНазвание и аннотация: Перевод в очереди
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Liu Zhaopei, Zhang Lingkai, Jin Kaifeng, Zeng Han, Su Xiaohe, Ding Yawei, Sun Jiaxing, Wu Yuzhen, Liu Hailong, Zhu Yu, Xu Le, Zhang Weijuan, Wang Zewei, Chang Yuan, Xu Jiejie
Аннотация
PURPOSE: ARID1A, encoding a component of the switch/sucrose nonfermentable complex, is frequently mutated in urothelial carcinoma. However, its specific impacts on clinical outcomes and CD8+ T-cell functions in urothelial carcinoma remain poorly understood.
EXPERIMENTAL DESIGN: The clinical relevance of ARID1A loss and CD8+ T-cell infiltration was evaluated in three cohorts [Zhongshan Hospital, Fudan University (ZSHS), n = 135; Fudan University Shanghai Cancer Center (FUSCC), n = 118; and IMvigor210, n = 274]. Immune microenvironment profiling was performed via IHC in the ZSHS cohort and transcriptomics in the IMvigor210 cohort. The Shanghai-sequencing cohort (n = 134) provided genomic characterization of ARID1A-loss patients.
RESULTS: ARID1A loss did not affect overall survival and CD8+ T-cell infiltration in both ZSHS and FUSCC cohorts. Only in ARID1A-loss urothelial carcinoma, high infiltration of CD8+ T cells yielded favorable outcomes (ZSHS cohort, log-rank P = 0.010; FUSCC cohort, log-rank P = 0.015). Moreover, ARID1Aloss CD8high patients displayed improved survival following adjuvant chemotherapy (log-rank P = 0.015) and PD-1/PD-L1 blockade (log-rank P = 0.020). In ARID1A-loss urothelial carcinoma, the enhanced antitumor function of CD8+ T cells might be affected by tertiary lymphoid structures. Furthermore, ARID1Aloss CD8high patients exhibited an antitumor immune contexture characterized by decreased immune-suppressive cells such as DC-SIGN+ tumor-associated macrophages, PDPN+ cells, and TGF-β+ cells, as well as lower expression of checkpoints such as B7-H3 and B7-H4.
CONCLUSIONS: The combination of ARID1A loss plus CD8+ T-cell infiltration indicated a favorable prognosis and responsiveness to both chemotherapy and immunotherapy. These findings provide valuable insights for developing novel therapeutic strategies and improving treatment stratification for urothelial carcinoma.
EXPERIMENTAL DESIGN: The clinical relevance of ARID1A loss and CD8+ T-cell infiltration was evaluated in three cohorts [Zhongshan Hospital, Fudan University (ZSHS), n = 135; Fudan University Shanghai Cancer Center (FUSCC), n = 118; and IMvigor210, n = 274]. Immune microenvironment profiling was performed via IHC in the ZSHS cohort and transcriptomics in the IMvigor210 cohort. The Shanghai-sequencing cohort (n = 134) provided genomic characterization of ARID1A-loss patients.
RESULTS: ARID1A loss did not affect overall survival and CD8+ T-cell infiltration in both ZSHS and FUSCC cohorts. Only in ARID1A-loss urothelial carcinoma, high infiltration of CD8+ T cells yielded favorable outcomes (ZSHS cohort, log-rank P = 0.010; FUSCC cohort, log-rank P = 0.015). Moreover, ARID1Aloss CD8high patients displayed improved survival following adjuvant chemotherapy (log-rank P = 0.015) and PD-1/PD-L1 blockade (log-rank P = 0.020). In ARID1A-loss urothelial carcinoma, the enhanced antitumor function of CD8+ T cells might be affected by tertiary lymphoid structures. Furthermore, ARID1Aloss CD8high patients exhibited an antitumor immune contexture characterized by decreased immune-suppressive cells such as DC-SIGN+ tumor-associated macrophages, PDPN+ cells, and TGF-β+ cells, as well as lower expression of checkpoints such as B7-H3 and B7-H4.
CONCLUSIONS: The combination of ARID1A loss plus CD8+ T-cell infiltration indicated a favorable prognosis and responsiveness to both chemotherapy and immunotherapy. These findings provide valuable insights for developing novel therapeutic strategies and improving treatment stratification for urothelial carcinoma.