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Published on: September 8, 2023
Genomic pathogenic alterations in the SWI/SNF complex compromise the outcomes of immunotherapy in Chinese patients
Lingling Gao1,2, Jie Jiang1,3, Linlin Zhu1,2
1Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Er Rd., Guangzhou, 510080, China.
Background:
Switch/sucrose nonfermentable (SWI/SNF) complex mutations have been reported in Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutant non-small cell lung cancer (NSCLC), but the influence on immune checkpoint blockade (ICB) outcomes is debated and needs to be investigated further.
Methods:
Genomic pathogenic alterations (GPAs) in SWI/SNF genes were identified via OncoKB, COSMIC and PolyPhen-2. NSCLC patients (NSCLCs) were classified according to alterations in six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4 and SMARCB1). Cell lines used for differentially expressed gene analyses were subjected to RNA sequencing (RNA-seq) and Western blotting to validate protein expression levels. Protein expression in tumour specimens was detected by immunohistochemistry (IHC).
Results:
In 2660 NSCLCs, 15.0% (401/2660) had SWI/SNF GPAs. A total of 23.1% (69/299) of the EGFRwtALKwt NSCLCs and 27.8% (25/90) of the STK11wtKEAP1wtKRASmut NSCLCs who received ICB had SWI/SNF GPAs. Among all the ICB-treated NSCLCs, progression-free survival (PFS) was not significantly different between SWI/SNF-wild type (wt) and SWI/SNF-mutant (mut) NSCLCs. However, GPAs in the SWI/SNF complex in KRAS-mut ICB-treated NSCLCs were associated with poorer clinical outcomes. Patients with ARID1A/ARID1B/ARID2/PBRM1 mutations had a significantly shorter PFS (2.7 vs. 6.5 m, HR = 2.44 [95% CI 1.31-4.54], P = 0.004) than did those with SWI/SNF-wt. Among STK11wtKEAP1wtKRASmut NSCLCs, all SWI/SNF-mut (4.9 vs. 9.1 m, HR = 2.03 [95% CI 1.07-3.86], P = 0.029) and ARID1A/ARID1B/ARID2/PBRM1-mut (3.2 vs. 9.1 m, HR = 2.68 [95% CI 1.33-5.41], P = 0.004) NSCLCs had significantly shortened PFS, and ARID1A/ARID1B/ARID2-mut NSCLCs also tended to have a shorter overall survival (OS) (12.2 vs. 29.9 m, HR = 2.20 [95% CI 0.98-4.91], P = 0.052). Furthermore, RNA-seq and Western blot analyses confirmed that the deletion of SWI/SNF genes resulted in downregulated STING expression in NSCLC cell lines. And IHC analysis of patient tumour samples confirmed that the loss of SWI/SNF protein expression was associated with decreased STING protein levels. Notably, downregulated STING protein expression was observed in KRAS-mut NSCLC patients who did not benefit from ICB treatment.
Conclusions:
In KRAS-mut NSCLCs with or without STK11/KEAP1 mutations, the GPAs in the DNA-binding genes ARID1A/ARID2 affected the outcomes of immunotherapy, possibly through the downregulation of STING expression.
Insights
Genomic alterations in SWI/SNF genes impact immunotherapy outcomes in KRAS-mutant non-small cell lung cancer (NSCLC). These mutations, particularly in ARID1A/ARID2, may reduce STING expression, correlating with poorer responses to immune checkpoint blockade (ICB).
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Switch/sucrose nonfermentable (SWI/SNF) complex mutations are observed in Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutant non-small cell lung cancer (NSCLC).
- The impact of SWI/SNF mutations on immune checkpoint blockade (ICB) efficacy in NSCLC remains debated and requires further investigation.
Purpose of the Study:
- To investigate the association between SWI/SNF gene mutations and ICB treatment outcomes in NSCLC patients.
- To explore the potential role of STING signaling in mediating the effects of SWI/SNF mutations on ICB response.
Main Methods:
- Genomic pathogenic alterations (GPAs) in six key SWI/SNF genes were identified in a cohort of NSCLC patients.
- Patients were classified based on SWI/SNF gene status and analyzed for progression-free survival (PFS) and overall survival (OS) following ICB treatment.
- RNA sequencing, Western blotting, and immunohistochemistry (IHC) were used to assess gene and protein expression, including STING levels.
Main Results:
- Approximately 15.0% of NSCLC patients harbored SWI/SNF GPAs, with higher prevalence in specific subsets receiving ICB.
- While overall PFS was not significantly different between SWI/SNF-wild type and mutant NSCLCs, KRAS-mutant NSCLCs with SWI/SNF mutations showed significantly poorer clinical outcomes.
- SWI/SNF gene deletions correlated with downregulated STING expression at both mRNA and protein levels, and reduced STING was observed in KRAS-mutant NSCLC patients unresponsive to ICB.
Conclusions:
- Genomic alterations in SWI/SNF genes, specifically in ARID1A/ARID2, significantly affect immunotherapy outcomes in KRAS-mutant NSCLC.
- The downregulation of STING expression is a potential mechanism through which SWI/SNF mutations influence ICB response in NSCLC.
- These findings highlight SWI/SNF mutations as potential predictive biomarkers for ICB therapy in KRAS-mutant NSCLC.
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