A “Lymphocyte MicroRNA Signature” as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming

Abstract

Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and after the nivolumab administration could represent a step toward a real-time monitoring of the dynamic changes during cancer evolution and treatment. Interestingly, we found a specific subset of miRNAs, called “lymphocyte miRNA signature”, specifically induced in long-responder patients (CR, PR, or SD to nivolumab >18 months). Focusing on the clinical translational potential of miRNAs in controlling the expression of immune checkpoints, we identified the association between the plasma levels of soluble PD-1/PD-L1 and expression of some lymphocyte miRNAs. These findings could help the development of novel dynamic predictive biomarkers urgently needed to predict the potential response to immunotherapy and to guide clinical decision-making in RCC patients.

Prognostic Role of Plasma PD-1, PD-L1, pan-BTN3As and BTN3A1 in Patients Affected by Metastatic Gastrointestinal Stromal Tumors: Can Immune Checkpoints Act as a Sentinel for Short-Term Survival?

“…Immune surveillance is often overridden by cancer cells due to the activation of immunomodulatory molecules such as programmed death protein (PD-1) and its ligand PD-L1, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), and butyrophilin sub-family 3A/CD277 receptors (BTN3A) [ 16 , 17 , 18 , 19 ]. In fact, in recent years, new and effective therapeutic options involving the use of drug agents targeting CTLA-4, PD-1, and PD-L1 were developed against several solid tumors, including melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC) [ 20 , 21 , 22 , 23 , 24 ]. Additionally, several investigations showed that anti-tumor immune responses may be positively or negatively modulated by immune checkpoints different from PD-1 and PD-L1 involved in the cross-talk between cancer and immune cells [ 25 ].…”

miR-224-5p Contained in Urinary Extracellular Vesicles Regulates PD-L1 Expression by Inhibiting Cyclin D1 in Renal Cell Carcinoma Cells

“…Recently, Incorvaia et al found that the expression of several miRNAs derived from peripheral lymphocytes of RCC patients was associated with the soluble levels of PD-1 and PD-L1 in plasma. These miRNA predictors could be used to discriminate responders of immunotherapy from non-responders [36]. This work also provides reliable clues to clarify the association of miRNA expression profile and PD-1/PD-L1 abundances in various EVs of RCC patients.…”

The molecular profiling of solid tumors by liquid biopsy: a position paper of the AIOM–SIAPEC-IAP–SIBioC–SIC–SIF Italian Scientific Societies

“…Recent studies evaluated the expression of plasma or serum levels of PD-L1, programmed cell death protein 1 (PD-1) and other immune checkpoints. 111 , 112 , 113 , 114 , 115 In these studies, elevated levels of the soluble form of PD-L1 (sPD-L1) were mainly associated with poor prognosis and worse clinical outcome. 116 , 117 , 118 Exosome PD-L1 has been also studied, showing how elevated concentrations of exosome PD-L1 in melanoma patients treated with immune checkpoint inhibitors (ICIs) were associated with worse prognosis.…”