Extracellular miRNAs as Predictive Biomarkers for Glypican-3-Derived Peptide Vaccine Therapy Response in Ovarian Clear Cell Carcinoma

SIMPLE SUMMARY: The prognosis of ovarian clear cell carcinoma was poor due to chemoresistance; therefore, immunotherapy, such as the glypican-3 (GPC3) peptide vaccine, gained attraction, as it prolonged survival. There were some super responders; however, response rates were limited because of the lack of predictive biomarkers for the efficacy of treatment. The purpose of this study was to explore circulating biomarkers using pre-treatment serum samples from a GPC3 peptide vaccine clinical trial in order to predict response to vaccine therapy. We identified serum miR-375-3p, miR-193a-5p, and miR-1228-5p as predictive biomarkers of response to GPC3 peptide vaccine therapy. These miRNAs were not overexpressed in tumor tissues, and functional annotation analysis suggested that these miRNAs were associated with interferon-related pathways. Therefore, these biomarkers may reflect the immune activity of patients and may have broader applications in all immune-related therapies, including tumor vaccines. ABSTRACT: Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.