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Published on: October 30, 2013
Clinical outcomes and immune contexture in SMARCA4-deficient gastric cancer patients
Mengyao Sun1, Yun Gu1,2, Jieti Wang3
1NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR China.
Abstract:
Exploiting vulnerabilities in switch/sucrose nonfermentable (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 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 gastric cancer (GC) patients. This study analyzed the association of SMARCA4 status with clinicopathological features, survival outcomes, therapeutic response, and 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). SMARCA4-deficient GC patients exhibit clinicopathological features associated with enhanced tumor aggressiveness, including a higher prevalence of poorly differentiated disease (p = 0.034), pN3 stage at diagnosis (p = 0.059), E-cadherin negative expression (p < 0.001), and 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 deficiency indicated poor prognosis in GC (p < 0.001). Moreover, SMARCA4 deficiency identified a subgroup of GC patients who exhibited poor outcomes despite receiving adjuvant chemotherapy in the GS subtype (p = 0.029). In contrast, these patients demonstrated increased sensitivity to anti-PD-1 therapy in both the ZSHS-ICB (p = 0.039) and SMC (p = 0.062) cohorts. Immunological analysis revealed a distinct immune profile characterized by abundant but exhausted CD8+ T cells in SMARCA4-deficient GC. In conclusion, patients with SMARCA4-deficient GC patients demonstrated poor prognosis but improved response to immunotherapy. These observed clinical outcomes may be attributed to the immunosuppressive microenvironment, highlighting the potential for developing novel therapeutic approaches. © 2025 The Pathological Society of Great Britain and Ireland.
Insights
SMARCA4-deficient gastric cancer (GC) patients show aggressive features and poor prognosis. However, these patients respond better to anti-PD-1 immunotherapy, suggesting potential therapeutic strategies targeting the tumor microenvironment.
Area of Science:
- Oncology
- Cancer Genomics
- Immunotherapy
Background:
- Switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes are crucial in cancer therapy.
- ARID1A loss in gastric cancer (GC) correlates with an immune-active microenvironment and better immunotherapy response.
- The clinical significance of SMARCA4, another SWI/SNF subunit, in GC remains largely unknown.
Purpose of the Study:
- To investigate the clinical significance of SMARCA4 deficiency in gastric cancer.
- To analyze the association of SMARCA4 status with clinicopathological features, survival, and immune microenvironment.
- To evaluate the therapeutic response to immunotherapy in SMARCA4-deficient GC.
Main Methods:
- Analysis of SMARCA4 status in three independent GC cohorts (ZSHS, ZSHS-ICB, SMC).
- Correlation analysis with clinicopathological features and survival outcomes using Kaplan-Meier.
- Assessment of immune microenvironment characteristics and response to anti-PD-1 therapy.
Main Results:
- SMARCA4-deficient GC exhibits aggressive features: poor differentiation, advanced pN3 stage, negative E-cadherin, and the microsatellite stable/epithelial-mesenchymal transition (MSS/EMT) subtype.
- SMARCA4 deficiency is linked to poor prognosis in GC and poor outcomes with chemotherapy in the genomically stable (GS) subtype.
- SMARCA4-deficient GC shows increased sensitivity to anti-PD-1 therapy and a distinct immune profile with abundant, exhausted CD8+ T cells.
Conclusions:
- SMARCA4 deficiency in GC indicates poor prognosis but predicts a better response to immunotherapy.
- The immunosuppressive tumor microenvironment in SMARCA4-deficient GC may explain these outcomes.
- Targeting SWI/SNF pathways and the immune microenvironment presents novel therapeutic opportunities for GC.
