Clinical outcomes and immune contexture in SMARCA4-deficient gastric cancer patients.

424 Background: Exploiting vulnerabilities in SWI/SNF chromatin remodeling complexes for cancer therapy is a promising therapeutic strategy. The SWI/SNF chromatin remodeling complex acts as a regulatory component of transcription, and our previous study has found an immune-active microenvironment and better response to immunotherapy of gastric cancer with ARID1A loss. However, little is known about the clinical significance of SMARCA4, which encodes for another subunit of the SWI/SNF complex, in GC patients. Methods: SMARCA4 status was evaluated by immunohistochemistry or genome sequencing. We analyzed the association of SMARCA4 status with clinicopathological features, survival outcomes, therapeutic response, as well as immune microenvironment characteristics in three independent cohorts: Zhongshan Hospital (ZSHS) cohort (n = 442), Zhongshan Hospital immune checkpoint blockade (ZSHS-ICB) cohort (n = 41) and Samsung Medical Center cohort (SMC, n = 51). Results: SMARCA4-deficient GC exhibit clinicopathological features associated with enhanced tumor aggressiveness, including a higher prevalence of poorly differentiated disease (P = 0.069), pN3 stage at diagnosis (P = 0.059), E-cadherin negative expression (P < 0.001), as well as genomically stable (GS) and microsatellite stable/epithelial–mesenchymal transition molecular subtype (MSS/EMT) (P < 0.001 and P < 0.001, respectively). Kaplan-Meier analysis revealed that SMARCA4 loss indicates poor prognosis in GC (P < 0.001). Moreover, SMARCA4 loss identifies a subgroup of GC patients with miserable outcome despite receiving adjuvant chemotherapy in the GS subtype (P = 0.029). Instead, these patients are more sensitive to anti-PD-1 treatment in both ZSHS-ICB (P = 0.039) and SMC (P = 0.062) cohorts. Immunological analysis revealed a distinct immune profile featured by substantial but exhausted CD8 + T Cells in SMARCA4-deficient GC. Conclusions: Patients with SMARCA4-deficient GC demonstrate poor prognosis but improved response to immunotherapy. The observed clinical outcomes may be attributed to the immunosuppressive microenvironment, highlighting the potential for novel therapeutic approaches.