ARID1A loss plus CD8+ T cell infiltration associate with favorable clinical outcomes in urothelial carcinoma

Abstract Purpose: ARID1A, encoding a component of the SWI/SNF complex, is frequently mutated in urothelial carcinoma (UC). However, its specific impacts on clinical outcomes and CD8+ T cell functions in UC remain poorly understood. Experimental Design: The clinical relevance of ARID1A loss and CD8+ T cell infiltration was evaluated in three cohorts (ZSHS, n = 135, FUSCC, n = 118, 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 the overall survival and CD8+ T cell infiltration in both ZSHS and FUSCC cohorts. Only in ARID1A-loss UC, high infiltration of CD8+ T cells yielded favorable outcomes (ZSHS cohort, Log-rank P = 0.010; FUSCC cohort, Log-rank P = 0.015). Moreover, ARID1A loss CD8 high 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 UC, the enhanced antitumor function of CD8+ T cells might be affected by tertiary lymphoid structures. Further, ARID1A loss CD8 high patients exhibited an antitumor immune contexture characterized by decreased immune suppressive cells such as DC-SIGN+ TAMs, PDPN+ cells, and TGF-β+ cells, as well as lower expression of checkpoints like 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 UC.