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RESEARCH PRODUCT

Finding the right biomarker for renal cell carcinoma (RCC): Nivolumab treatment induces the expression of specific peripheral lymphocyte microRNAs in patients with durable and complete response

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Abstract Background 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. Methods 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 12 months (P2). Results 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. Conclusions 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 ( Legal entity responsible for the study The authors. Funding Department of Surgical, Oncological and Oral Sciences, University of Palermo. Disclosure All authors have declared no conflicts of interest.