1723P CLEC3B mRNA expression levels are linked to distinct genetic backgrounds, transcriptomic signatures and survival in NSCLC

Abstract

Downregulated C-type lectin domain family 3 member B (CLEC3B) is observed in NSCLC and is linked with immune cell infiltration. We aimed to analyse the impact of CLEC3B mRNA expression on survival and its molecular link to NSCLC subtypes and to immune cell infiltration. 19,892 samples were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes/WES), RNA (WTS) and IHC. Top quartile transcripts per million (TPM) were defined as high (Q4, ≥4.03 TPM) and bottom quartile as low (Q1, ≤0.89 TPM). Cell infiltration was estimated by QuantiSEQ. X2/Fisher-Exact were used and significance was determined as p-value adjusted for multiple comparison (q<0.05). Real-world overall survival (OS) information was obtained from insurance claims data. Median age was 69 years. High CLEC3B mRNA expression was associated with female sex (55.2% women vs 44.8% men, p<0.001). Adenocarcinomas vs squamous-cell carcinomas had higher CLEC3B expression (2.28 vs 1.51, q<0.001). CLEC3B correlated negatively with mutations in TP53 (74.7% in Q1 vs 52.4% in Q4), KEAP1 (15.9% vs 11.2%), RB1 (13.5 vs 9.2%), CDKN2A (13.0% vs 8.3%), NF1 (10.3% vs 6.9%) (all q<0.001). KRAS (31.8% in Q4 vs 25.6% in Q1), EGFR (17.2% vs 8.1%), STK11 (15.9% vs 11.3%) mutations were more frequently observed in CLEC3B high expressors (all q<0.001). High CLEC3B mRNA expression was negatively associated with high TMB (43.0% vs 29.0%) and high PD-L1 expression (62.5% vs 47.7%) (all q<0.05). Transcriptomics revealed an upregulation of various immunological markers (i.e. LAG3, INF-G, PDCD1) and a higher abundance of several immune cells (i.e. B cells, macrophages, T cells) in the CLEC3B high subgroup (all q<0.001). Patients with high CLEC3B mRNA expression showed an improved OS when compared to CLEC3B low expression (p<0.001, HR: 1.35); a similar observation was made in patients treated with checkpoint inhibitors (p<0.001, HR: 1.29). Our study represents the largest analysis of CLEC3B mRNA expression in NSCLC. High CLEC3B expression levels are linked to a distinct molecular/immunological profile and to improved survival. Further experiments are now ongoing to unravel functional aspects of CLEC3B biology in NSCLC.