Plasma exosomes contain microRNAs that reflect disease status during and after treatment

The peripheral blood of patients with malignancies is enriched with circulating extracellular vesicles (EV) such as exosomes that enclose microRNAs (miRNA) from their cell of origin. We generated RNAseq profiles from exosomal-miRNAs in multiple cancer types and show that exosome-bound miRNAs distinghuish cancer types and can serve as treatment response indicators for patients with classical Hodgkin Lymphoma (cHL).

Unsupervised clustering of complete cHL miRNA profiles separates pre- and during treatment positron emission tomography/computed tomography scan (PET-CT) positive samples from complete (metabolic) response samples. We performed quantitative RT-PCR on blood samples from 31 cHL patients and validated miR155-5p, miR24-3p, miR127-3p, miR21-5p and Let7a-5p as cHL biomarkers. Pre-treatment EV-miRNA concentrations are significantly higher in active disease samples compared to healthy controls and drop rapidly upon treatment in complete responders, remaining stable in individuals at low levels for years. The plasma levels of the EV-miRNAs in our panel have no meaningful relationship with age, gender, liver or kidney functions but correlate to a minor extent with blood leukocyte and thrombocyte counts. This suggests that the elevated levels of cHL miRNAs are derived from diseased nodes and not from circualting blood cells. Random effects modeling indicates that a miR127-3p/miR24-3p combination is a good predictor for determining ‘absence of active disease nodes’ with a negative-predictive value (NPV) of 86%. Notably, combining miR127-3p with serum TARC (sTARC), a cHL-associated chemokine, increased the NPV to 96%.

Our results suggest that a multi-analyte assay combining exosomal-miRNAs with protein biomarkers has potential to determine whether patients with cHL could be spared unnecessary continuation of treatment. More general our work provides a new rationale for the clincial utility of circulating miRNAs.