CircRNome-wide characterisation reveals the promoting role of circAATF in anti-PD-L1 immunotherapy of gallbladder carcinoma

Abstract

Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4⁺ T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4⁺ T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy.

Highlights

• We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC).

• CircAATF is positively associated with CD4⁺ T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model.

• CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.