ARID1A Loss plus CD8+ T-Cell Infiltration Associate with Favorable Clinical Outcomes in Urothelial Carcinoma

Abstract 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.