Cisplatin-Induced Rab27A/B Exosomal PD-L1 Axis Suppresses Antitumor Immunity and Correlates with Poor 5-Year Survival in Lung Squamous Cell Carcinoma and Adenocarcinoma.

Current research primarily focuses on post-treatment resistance, leaving the immediate impact of cisplatin on the tumor-immune interaction poorly understood. Tumor cells were co-cultured with immune cells to assess immune cell activation. The correlation with RAB27A/B and CD274 expression levels in non-small cell lung cancer (NSCLC) were analyzed using TCGA. The relationship between RAB27A/B and the tumor microenvironment was assessed by TIMER2.0. Cisplatin significantly increased PD-L1 mRNA levels and surface protein expression, detected by qPCR, flow cytometry and confocal microscopy. In the co-culture assay, cisplatin-induced cell surface PD-L1 protein levels inhibited the activation of Jukat T-cells. Cisplatin also upregulated genes associated with exosome secretion and increased total exosome particle counts and secretion per cell. Pretreatment with GW4869, an exosome release inhibitor, significantly enhanced cisplatin sensitivity in HCC827 cells. While GW4869 reduced intracellular RAB27A/B and EV PD-L1 levels, it did not alter cellular PD-L1 expression. Bioinformatic analysis further revealed that high RAB27A/B expression correlates with poor 5-year survival in NSCLC and is negatively associated with CD8+ T-cell activation, while positively correlating with cancer-associated fibroblasts. Both RAB27A and RAB27B gene expression levels positively correlated with CD274. Conclusions: RAB27A and RAB27B may be crucial proteins in modulating cisplatin-induced exosomal PD-L1 levels and the tumor microenvironment.