Exosomal circPPP2R2D stimulates CD8+ T cell dysfunction and anti‑PD1 resistance in lung adenocarcinoma

Background : Circular RNAs (circRNAs) in exosomes are implicated in cell-cell communications, including those affecting the malignant progression of various cancers. Exosomal circRNAs affect CD8+ T cell dysfunction in lung adenocarcinoma (LUAD); however, the underlying mechanism is unclear. Methods : CD8+ T cell dysfunction in the presence of circPPP2R2D was examined by flow cytometry and Western blotting. Chromatin immunoprecipitation, biotinylated RNA pulldown, RNA immunoprecipitation, and MS2 pulldown assays were performed to determine the mechanism of circPPP2R2D activity. Furthermore, a mouse model with reconstituted human immune system components (huNSG mice) was established to analyze the impact of exosomal circPPP2R2D on anti-PD1 resistance in LUAD. Results : Plasma-derived exosomes contained high levels of circPPP2R2D. Moreover, circPPP2R2D expression was upregulated in tumor tissues from patients with LUAD and LUAD cell lines. CircPPP2R2D promoted LUAD development and migration both in vitro and in vivo . While eukaryotic translation initiation factor 4A3 and E1A binding protein p300 upregulated circPPP2R2D, Hu antigen R-induced m6A modification promoted its stability through combination with insulin-like growth factor 2 mRNA-binding protein 3. Additionally, heterogeneous nuclear ribonucleoprotein A2/B1 influenced circPPP2R2D production in LUAD cells. In CD8+ T cells, absorption of circPPP2R2D-containing exosomes induced dysfunction through enhanced PD-1 protein stabilization, increasing anti-PD1 immunotherapy resistance. Conclusions : Exosomal circPPP2R2D released by LUAD cells aggravates CD8+ T cell dysfunction through enhanced immunosuppression. CircPPP2R2D increases resistance to anti-PD1 immunotherapy and represents a potential therapeutic target for LUAD treatment.