Identification of SLIT3 mutation as a response biomarker for immune checkpoint inhibitor therapy in non-small cell lung cancer

Finding non-small cell lung cancer (NSCLC) patients who potentially benefit from immune checkpoint inhibitors (ICIs) is a crucial and challenging process in immunotherapy. Investigating predictive biomarkers may make it possible to maximize the therapeutic advantages. It has been established that SLIT3 is crucial for tumor immunity. However, the association between SLIT3 gene mutation and ICI response is lacking. To analyze the performance of SLIT3 mutation as an indicator stratifying beneficiaries of ICIs, two public cohorts with whole-exome sequencing (WES) data (Hellmann and Rizvi cohorts) were enrolled. The mechanism was explored based on TCGA-LUAD, TCGA-LUSC and Oncosg cohorts. The SLIT3-MUT group had a longer progression-free survival (PFS) compared to the SLIT3-WT group in the Hellmann cohort (12-month PFS: MUT vs. WT, 62.5% vs. 33.4%, p = 0.031) and the Rizvi cohort (MUT vs. WT, 75.0% vs. 27.9%, p = 0.049). The patients with SLIT3-MUT exhibited a significantly higher ORR compared to those with SLIT3-WT in the Hellmann cohort (MUT vs. WT, 79.0% vs. 30%; OR = 5.25, 95% CI: 1.01–27.36, P = 0.039) and the Rizvi cohort (MUT vs. WT, 100.0% vs. 56.6%; OR = 17.27, 95% CI: 0.92–324.58, P = 0.028). In addition, the tumor mutational burden (TMB), silent mutation rate and SNV neoantigens were higher in SLIT3-MUT compared to SLIT3-WT. Moreover, SLIT3 mutation was correlated with enhanced anti-tumor immunity including higher activated CD4 memory T cells level, higher CD8 + T cells level, and upregulated DNA damage repair pathways. Our results suggested that SLIT3 mutation may be a useful marker to identify NSCLC patients who may benefit most from ICI therapy, which warrants future prospective research.