Plasma extracellular vesicle transcriptomics identifies CD160 for predicting immunochemotherapy efficacy in lung cancer.

Better biomarkers are needed to improve the efficacy of immune checkpoint inhibitor in lung adenocarcinoma (LUAD) treatment. We investigated the plasma EV-derived long RNAs (exLRs) in unresectable/advanced LUAD to explore biomarkers for immunochemotherapy. A total of 74 LUAD patients without targetable mutations receiving first-line anti-PD-1 immunochemotherapy were enrolled. Their exLRs were profiled through plasma EV transcriptome sequencing. Biomarkers were analyzed against response rate and survival using pre- and post-treatment samples in the retrospective cohort (N=36) and prospective cohort (N=38). Results showed that LUAD patients demonstrated a distinct exLR profile from the healthy individuals (N=56) and T-cell activation-related pathways were enriched in responders. Among T-cell activation exLRs, CD160 exhibited a strong correlation with survival. In retrospective cohort, the high baseline EV-derived CD160 level correlated with prolonged PFS (P<0.001) and OS (P=0.005), with an AUC of 0.784 for differentiating responders from non-responders. In prospective cohort, the CD160-high patients also showed prolonged PFS (P=0.003) and OS (P=0.014), and a promising AUC of 0.648. The predictive value of CD160 expression was validated by RT-qPCR. We also identified the dynamics of EV-derived CD160 for monitoring therapeutic response. The elevated baseline CD160 reflected a higher abundance of circulating NK cells and CD8+ naïve T cells, suggesting more active host immunity. In addition, increased CD160 levels of tumor also correlated with a favorable prognosis in LUAD patients. Together, plasma EV transcriptome analysis revealed the role of the baseline CD160 level and early post-treatment CD160 dynamics for predicting response to anti-PD-1 immunochemotherapy in LUAD patients.