A novel prognostic model based on 4 circulating miRNAs in diffuse large B-cell lymphoma: implications for the roles of MDSCs and Th17 cells in lymphoma progression.

MicroRNAs (miRNAs) have been emerged as prognostic biomarkers in diffuse large B-cell lymphoma (DLBCL). To understand the potential underlying mechanisms and translate these findings into clinical prediction on lymphoma progression, large patient cohorts should be evaluated. Here, using miRNA PCR array, we analyzed the miRNA expression profiles in serum samples of 20 DLBCL patients at diagnosis, remission, and at relapse. Four candidate miRNAs were identified and subsequently evaluated for their ability to predict relapse and survival. A prognostic model based on four circulating miRNAs (miR21, miR130b, miR155, and miR28) was established and tested in the training cohort of 279 patients and in the validation cohort of 225 patients (NCT01852435). The prognostic value of the 4-miRNA model was assessed by univariate and multivariate analyses. The novel 4-miRNA prognostic model significantly predicted clinical outcome of DLBCL, independent of International Prognostic Index in the training cohort [HR=2.83 (95%CI 2.14-3.51), P<0.001] and in the validation cohort [HR=2.71 (95%CI 1.91-3.50), P<0.001]. Moreover, DNA- and RNA-sequencing were performed on tumor samples to detect genetic mutations and signaling pathway dysregulation. DNA-sequencing data showed no significant difference of tumor mutation burden between the low-risk and the high-risk groups of the 4-miRNA model. RNA-sequencing revealed a correlation between the 4-miRNA model and aberrant Ras protein signaling transduction. The impact of the miRNA signature on oncogenic signaling and tumor microenvironment was analyzed in vitro and in vivo. In B-lymphoma cells, modulation of the miRNAs regulated IGF1 and JUN expression, thereby altering MDSCs and Th17 cells. In DLBCL patients, the high-risk group presented Ras signaling activation, increased MDSCs and Th17 cells, and immunosuppressive status compared to the low-risk group. In conclusion, the easy-to-use 4-miRNA prognostic model effectively predicted relapse and survival in DLBCL. Moreover, the tumor microenvironment contributes to the role of the 4-miRNA model on DLBCL progression.