Genomic pathogenic alterations in the SWI/SNF complex compromise the outcomes of immunotherapy in Chinese patients with KRAS-mutant NSCLC by downregulating STING expression.

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 EGFR(wt)ALK(wt) NSCLCs and 27.8% (25/90) of the STK11(wt)KEAP1(wt)KRAS(mut) 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 STK11(wt)KEAP1(wt)KRAS(mut) 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.