CircSCUBE3 Reduces the Anti-gastric Cancer Activity of Anti-PD-L1

Abstract

The progression of gastric cancer (GC) is closely related to tumor immune escape. The research, therefore, studied the impact of possible circRNAs on the immune escape of GC tumors and the underlying mechanisms. Here, to explore circRNAs that may affect GC, the differential circRNAs in six normal gastric mucosal tissues and six GC samples (GSM2005868-GSM2005879) were analyzed through the bioinformatics website circmine, and hsa_circ_0076092 (circSCUBE3) was identified as the research object. In vitro assays revealed the functions of circSCUBE3 and its downstream miRNA/mRNA axis in GC cells. The effect of circSCUBE3 against PD-1 anti-tumor activity was evaluated in vivo. The relationship between circSCUBE3 and miR-744-5p, miR-744-5p, and SLC7A5 was identified by RNA immunoprecipitation and dual-luciferase reporter experiments. The effect of SLC7A5 on GC immune escape by regulating PD-L1 expression was assessed by co-culture system and flow cytometry. CircSCUBE3 was up-regulated in human GC tissues and GC cell lines. circSCUBE3 was associated with poor prognosis in GC patients. Functional experiments reported that circSCUBE3 knockdown could suppress GC immune escape. Mechanistically, circSCUBE3 bound to miR-744-5p, which further targeted SLC7A5, and SLC7A5 can affect GC immune escape by regulating PD-L1. Furthermore, in vivo assay manifested that circSCUBE3 attenuated the anti-tumor effect of PD-L1. Our study revealed the importance of the circSCUBE3/miR-744-5p/SLC7A5 axis in GC immune escape and anti-PD-1 resistance.

Keywords: CircSCUBE3; Gastric cancer; PD-1; SLC7A5; Tumor immune escape; miR-744-5p.