Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma

Abstract

MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL), where they reflect the malignant B-cells and the immune infiltrate within the tumor microenvironment. There remains a paucity of data in DLBCL regarding cell-free (c-f) miRNA as disease response biomarkers. Immunosuppressive monocyte/macrophages, which are enriched in DLBCL, are disease response markers in DLBCL, with miRNA key regulators of their immunosuppressive function. Our aim was to determine whether plasma miRNA that reflect the activity of the malignant B-cell and/or immunosuppressive monocytes/macrophages, have value as minimally-invasive disease response biomarkers in DLBCL.Quantification of 99 DLBCL tissues, to select miRNA implicated in immunosuppressive monocytes/macrophage biology, found miR-494 differentially elevated. In a discovery cohort (22 patients), pre-therapy c-f miR-494 and miR-21 but not miR-155 were raised relative to healthy plasma. Both miR-494 and miR-21 levels 3-6 months reduced post immuno-chemotherapy. The validation cohort (56 patients) was from a prospective clinical trial. Interestingly, in sequential samples both miRNAs decreased in patients becoming Positron Emission Tomography/Computerized Tomography (PET/CT)-ve, but not in those remaining interim-PET/CT+. Patient monocytes were phenotypically and functionally immunosuppressive with ex-vivo monocyte depletion enhancing T-cell proliferation in patient but not healthy samples. Pre-therapy monocytes showed an immunosuppressive transcriptome and raised levels of miR-494. MiR-494 was present in all c-f nanoparticle fractions but was most readily detectable in unfractionated plasma.Circulating c-f miR-494 and miR-21 are disease response biomarkers with differential response stratified by interim-PET/CT in patients with DLBCL. Further studies are required to explore their manipulation as potential therapeutic targets.

The Interplay between MicroRNAs and the Components of the Tumor Microenvironment in B-Cell Malignancies

“…Studies on these immune suppressor cells showed that several miRNAs, such as miR-494, miR-21, miR-30a, miR-155, miR-17-5p, miR-20a, miR-690, and miR-101, could regulate the proliferation, differentiation, and activation of these myeloid cells [59][60][61][62]. In the study by Cui et al, the elevated plasma levels of the MDSCs-associated-miRNAs, miR-494 and miR-21, in DLBCL patients profoundly decreased following 3-6 months of conventional first-line immuno-chemotherapy [58]. Moreover, the kinetic of the reduction of miR-494 expression level was associated with the interim-PET/CT status of the patients.…”

“…However, miRNAs originating from non-malignant tumor-infiltrating cells could also reflect the disease response [57]. MiRNAs that are implicated in regulating the activity of the immunosuppressive components of TME, such as monocytic myeloid-derived suppressor cells (moMDSCs) and tumor-associated macrophages (TAMs), are considered disease response biomarkers in patients with DLBCL [58]. MDSCs are a diverse group of non-lymphoid immune suppressor cells deriving from the myeloid lineage and they function by orchestrating the TME and suppressing anti-tumor immune responses.…”

Bringing MicroRNAs to Light: Methods for MicroRNA Quantification and Visualization in Live Cells

“…Activity, localization and distribution of miRNA are disease biomarkers (Cheng et al, 2015 ; Cui et al, 2018 ), and the above mentioned methods effectively visualize miRNAs in patients as non-invasive imaging systems.…”

Circulating RNA biomarkers in diffuse large B-cell lymphoma: a systematic review

“…As diagnostic biomarkers in DLBCL, a total of eight different miRNAs (miR-15a, miR-21, miR-29c, miR-34a, miR-145, miR-155, miR-210, and miR-375) were found to be significantly dysregulated in at least two different studies. The studies concerning miR-145, miR-375, miR-15a, miR-21 and miR-155 presented the most concordant results, the first two miRNAs being lower and the following three being higher in DLBCL [53,[55][56][57][58][59][60][61][62][63][64][65]. MiR-145 and miR-375 were lower in two studies and are considered tumor suppressors in different cancer types.…”