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Published on: June 16, 2018
SMARCA4-deficient lung carcinoma is an aggressive tumor highly infiltrated by FOXP3+ cells and neutrophils
Yoan Velut1, Elise Decroix1, Hélène Blons2
1Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Team Inflammation, Complement and Cancer, F-75006 Paris, France.
Introduction:
SMARCA4/BRG1 loss of expression occurs in 5-10% of non-small cell lung carcinomas (NSCLC). We investigated the pathological, molecular and immune environment characteristics of this deficiency among NSCLC, its impact on overall survival (OS) of resected patients and the sensitivity to anti-PD1 inhibitors in metastatic patients.
Materials And Methods:
BRG1 expression was assessed by immunohistochemistry to identify SMARCA4-deficient NSCLC (SD-NSCLC) from the cancer tissue collection of Cochin Hospital (Paris, France). Molecular profiles were analyzed by targeted NGS covering 28 genes in 63 resected SD-NSCLC. The balance of immune cells between CD8+, FOXP3+ cells and neutrophils (CD66b+) was characterized by multiplex immunohistochemistry and compared to non-SD NSCLC. Clinical outcome after anti-PD-1 therapy was evaluated in 7 SD-NSCLC out of 77 NSCLC patients.
Results:
SD-NSCLCs were more commonly found in TTF1-negative high-grade adenocarcinomas and pleomorphic carcinomas. They were associated with few targetable alterations (KRAS G12C and MET amplification). Their immune environment was characterized by an increased of FOXP3+ cell and neutrophil densities, but not of CD8+ T cells, compared to non-SD NSCLC. SD-NSCLC patients had a significantly shorter OS in early stages of resected patients and in metastatic patients treated by anti-PD1 treatment.
Conclusion:
BRG1-loss in NSCLC confers a poor prognosis and is associated with an immunosuppressive environment that could be responsible of limited efficacy to anti-PD1 inhibitors. The identification of SD-NSCLC by BRG1 immunohistochemistry is desirable for an optimal management of NSCLC patients.
Insights
SMARCA4/BRG1 loss in non-small cell lung cancer (NSCLC) is linked to poorer survival and a less responsive immune environment, potentially limiting anti-PD-1 therapy effectiveness. Identifying this deficiency is crucial for patient management.
Area of Science:
- Oncology
- Immunology
- Pathology
Background:
- SMARCA4/BRG1 loss occurs in 5-10% of non-small cell lung carcinomas (NSCLC).
- This deficiency impacts tumor characteristics and patient prognosis.
- Understanding the immune microenvironment is key to predicting treatment response.
Purpose of the Study:
- To characterize pathological, molecular, and immune features of SMARCA4-deficient NSCLC (SD-NSCLC).
- To assess the impact of SD-NSCLC on overall survival (OS) in resected patients.
- To evaluate the sensitivity of SD-NSCLC to anti-PD-1 inhibitors in metastatic patients.
Main Methods:
- Immunohistochemistry (IHC) for BRG1 expression to identify SD-NSCLC.
- Targeted next-generation sequencing (NGS) for molecular profiling.
- Multiplex IHC to analyze immune cell populations (CD8+, FOXP3+, neutrophils).
- Clinical outcome analysis for resected and metastatic NSCLC patients.
Main Results:
- SD-NSCLC predominantly found in TTF1-negative, high-grade adenocarcinomas and pleomorphic carcinomas.
- Associated with limited targetable alterations (e.g., KRAS G12C, MET amplification).
- Characterized by increased FOXP3+ cells and neutrophils, but not CD8+ T cells.
- Significantly shorter OS in early-stage and metastatic anti-PD-1 treated patients.
Conclusions:
- BRG1 loss in NSCLC indicates a poor prognosis.
- SD-NSCLC exhibits an immunosuppressive tumor microenvironment.
- This microenvironment may explain the limited efficacy of anti-PD-1 inhibitors.
- BRG1 IHC is recommended for optimal NSCLC patient management.
