Plasma Exosomal miRNAs as Response Biomarkers of Immunotherapy in Extensive-Stage Small-Cell Lung Cancer

Abstract

Immunotherapy combined with chemotherapy has become the first-line standard treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). The reliable biomarkers stratifying true responders of immunotherapy effectively are unknown, and it is urgent to identify novel biomarkers in clinical. Exosomal miRNAs are considered to play a role in intercellular communication among immune cells and interaction between immune cells and tumor cells. The purpose of this study was to explore the possibility of using plasma-derived exosomal miRNAs as potential biomarkers for identifying responses to immunotherapy in ES-SCLC. From March 2020 to September 2021, 24 patients with ES-SCLC who received PD-L1 inhibitors were enrolled. Tumor assessments were conducted after every two treatment cycles according to RECIST 1.1. Plasma samples of these patients were collected before administering PD-L1 inhibitors as the baseline, and after every four cycles until the occurrence of disease progression. Plasma exosomes were isolated by ultracentrifugation, then total RNA was extracted. The miRNA profile was analyzed with small RNA next-generation sequencing followed by differential expression analysis. Of the 24 patients, 15 underwent immunotherapy maintenance after completing four cycles of PD-L1 inhibitor plus chemotherapy. In order to identify biomarkers for a better response to immunotherapy, all five responders (patients achieving PR) and four non-responders (patients achieving PD) at tumor assessment within eight cycles of the maintenance phase were included for differential expression analysis. Surprisingly, hsa-miR-320c, hsa-miR-320d, and hsa-miR-320e showed a trend of increased expression in the non-responders compared with the responders at baseline and were significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the responders. Exosomal miRNA profiles are discordant between responders and non-responders of anti-PD-L1 treatment. Hsa-miR-320c, hsa-miR-320d, and hsa-miR-320e were identified as potential biomarkers for predicting the efficacy of immunotherapy in patients with ES-SCLC.