Circulating extracellular vesicle-derived lncRNA-GC1 serves as a novel biomarker for predicting and monitoring gastric cancer patient immunotherapeutic outcomes

Abstract Background Efforts to predict patient outcomes following immune checkpoint inhibitor (ICI) treatment remain limited owing to a lack of any reliable prognostic biomarkers. In prior studies, circulating extracellular vesicle (EV)-derived lncRNA-GC1 was found to offer value as a gastric cancer (GC)-specific biomarker that could be used for the early diagnosis and subsequent monitoring of affected patients. This study was developed with the goal of expanding on these prior results by assessing the utility of EV-derived lncRNA-GC1 as a predictive biomarker associated with the outcomes of GC patients undergoing ICI treatment. Methods qPCR was used to measure EV-derived lncRNA-GC1 levels in patient samples, while correlations between the levels of this lncRNA and therapeutic outcomes were analyzed for GC patients undergoing ICI treatment in both a training cohort (n = 84), two separate validation cohorts (n = 124 and n = 131), and one prospective cohort (n = 80). Lastly, the stability of EV-derived lncRNA-GC1 was assessed in a distinct retrospective patient cohort (n = 30). Results EV-derived lncRNA-GC1 levels were independent of the PD-L1 expression status or density of CD8 + T cell infiltration observed for GC patients. Baseline EV-derived lncRNA-GC1 levels were able to effectively predict patient immunotherapeutic outcomes and could be used for the dynamic monitoring of GC patients over the course of treatment. Lower EV-derived lncRNA-GC1 levels were associated with microenvironmental characteristics of more robust antitumor immunity including higher levels of activated CD8 + T/NK cells and an increased TH1/TH2 ratio. Such EV-derived lncRNA-GC1 could also be stably detected in clinical samples even after they had undergone repeated freeze/thaw cycles or prolonged incubation at room temperature. These results were also consistent across multiple training and validation cohorts. Conclusions Here, EV-derived lncRNA-GC1 was found to reliably predict immunotherapeutic responses in GC patients undergoing ICI-related therapy, suggesting that targeted analyses of this lncRNA may be ideal as a tool to guide patient treatment planning, monitoring, and related decision-making, in addition to offering new insights with the potential to improve GC patient immunotherapy outcomes.