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

Better biomarkers are needed to improve the efficacy of immune checkpoint inhibitors in lung adenocarcinoma (LUAD) treatment. We investigated the plasma extracellular vesicle (EV)‐derived long RNAs (exLRs) in unresectable/advanced LUAD to explore biomarkers for immunochemotherapy. Seventy‐four LUAD patients without targetable mutations receiving first‐line anti‐programmed cell death 1 (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). The 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 the retrospective cohort, the high baseline EV‐derived CD160 level correlated with prolonged progression‐free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.005), with an area under the curve (AUC) of 0.784 for differentiating responders from non‐responders. In the 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 real‐time quantitative PCR. 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 tumors 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 the response to anti‐PD‐1 immunochemotherapy in LUAD patients.