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

MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL),where they reffect the malignant B-cells and the immune infltrate within the tumormicroenvironment. 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 todetermine whether plasma miRNA that reffect the activity of the malignant B-cell and/or immunosuppressive monocytes/macrophages, have value as minimally-invasivedisease response biomarkers in DLBCL.Quantifcation of 99 DLBCL tissues, to select miRNA implicated in immunosuppressivemonocytes/macrophage biology, found miR-494 differentially elevated. In a discoverycohort (22 patients), pre-therapy c-f miR-494 and miR-21 but not miR-155 were raisedrelative to healthy plasma. Both miR-494 and miR-21 levels 3-6 months reduced postimmuno-chemotherapy. The validation cohort (56 patients) was from a prospectiveclinical trial. Interestingly, in sequential samples both miRNAs decreased in patientsbecoming Positron Emission Tomography/Computerized Tomography (PET/CT)-ve,but not in those remaining interim-PET/CT+. Patient monocytes were phenotypicallyand functionally immunosuppressive with ex-vivo monocyte depletion enhancing T-cellproliferation in patient but not healthy samples. Pre-therapy monocytes showed animmunosuppressive transcriptome and raised levels of miR-494. MiR-494 was present inall c-f nanoparticle fractions but was most readily detectable in unfractionated plasma.Circulating c-f miR-494 and miR-21 are disease response biomarkers withdifferential response stratifed by interim-PET/CT in patients with DLBCL. Furtherstudies are required to explore their manipulation as potential therapeutic targets.