Slit mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.

Abstract

e14572 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlyingpredictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Slits (Slit1, 2 and 3) are highly conserved secreted glycoproteins that play important roles in tumorigenesis, including cancer cell proliferation, motility and angiogenesis. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between SLIT and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between SLIT gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with SLIT mutation were significantly associated with better PFS (HR = 0.27; 95% CI, 0.14-0.52; P < 0.001), objective response rate (ORR, 63.3% vs 25.2%; P < 0.001) and durable clinical benefit (DCB, 86.7% vs 63.0%; P = 0.048) after ICIs therapy, compared with those with wide-type SLIT. SLIT mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between SLIT mutation and PFS remained significant (HR = 0.38; 95% CI, 0.19-0.77; P = 0.007). In contrast, no association between SLIT mutation and OS (LUAD: P = 0.57 ; LUSC: P= 0.1) or PFS (LUAD: P = 0.71; LUSC: P = 0.55) was observed in TCGA datasets, suggesting that SLIT mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, SLIT mutation was significantly associated with higher naive B cell, plasma B cell, activated memory CD4+ T cell, CD8+ T cell, as well as lower M2 macrophage and Treg cell. Moreover, SLIT mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. In addition, GSEA analysis revealed that SLIT mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway and activation of NF-κB in B-cell. Conclusions: Our results demonstrated that SLIT mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of SLIT in immunotherapy is needed to be further studied.