The variability of clinical response to immune checkpoint inhibitors in RCC patients makes necessary the discovery of predictive biomarkers for patient selection. Emerging evidence has revealed a multitude of silenced genes and deregulated signalling pathways. These findings point towards extensive microRNAs (miRNAs) regulation and imply epigenetic reprogramming as a key feature of RCC. The aim of this study was to analyze the peripheral lymphocyte miRNA expression profile in metastatic RCC patients undergoing nivolumab treatment, to identify a lymphocyte miRNA signature specifically expressed in patients with partial or complete response (RP; RC) >12 months.
miRNAs were isolated from peripheral lymphocytes of 18 mRCC patients treated with nivolumab as 2nd line. The blood samples were collected before starting treatment (T0) and after 4 weeks (T1). The expression profile of 377 miRNAs was analyzed, with a cut off of fold change >2 for up-regulated and <0.3 for down-regulated miRNAs. Patients were divided into 2 groups: i) patients with disease progression (PD) within 6 months of treatment (P1); ii) patients with durable response (SD, RP, RC) >12 months (P2).
Microarray analysis showed several differentially expressed miRNAs in peripheral lymphocytes of P1 and P2, involved in RCC signaling pathways such as VHL-HIF, PI3K/Akt, PTEN and WNT-β-catenin. Surprisingly, patients with RC > 12 months showed a subset of 8 miRNAs (miR-24, miR-22, miR-99a, miR-708, miR-339, miR-335, miR-214, miR-194) specifically induced by nivolumab treatment. These miRNAs are silenced or downregulated in RCC. This could explain the exceptional up-regulation in long-responder patients, evident already after 4 weeks of treatment.
Our study for the first time analyzed the miRNA expression profile in peripheral lymphocytes and showed the exceptional up-regulation of a specific subset of miRNA only in RCC patients with durable (<12 months) and complete response to nivolumab treatment. These findings could help to identify novel predictive biomarkers urgently needed to guide clinical decision-making in RCC patients.
Clinical trial identification
Legal entity responsible for the study
Department of Surgical, Oncological and Oral Sciences, University of Palermo.
All authors have declared no conflicts of interest.