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
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Qingyan Cui1, Frank Vari1, Alexandre S. Cristino1, Carlos Salomon2,3, Gregory E. Rice2, Muhammed B. Sabdia1, Dominic Guanzon2, Carlos Palma2, Marina Mathew1, Dipti Talaulikar4,5, Sanjiv Jain4, Erica Han1, Mark S. Hertzberg6, Clare Gould1, Pauline Crooks1, Gayathri Thillaiyampalam1, Colm Keane1,7 and Maher K. Gandhi1,7
1University of Queensland Diamantina Institute, Brisbane, QLD, Australia
2University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia
3University of Concepción, Concepción, Chile
4Canberra Hospital, Garran, ACT, Australia
5Australia National University Medical School, Garran, ACT, Australia
6Prince of Wales Hospital, Sydney, NSW, Australia
7Princess Alexandra Hospital, Brisbane, QLD, Australia
Qingyan Cui, email: Q.Cui@uq.edu.au
Maher K. Gandhi, email: M.Gandhi@uq.edu.au
Keywords: miRNA-494; miRNA-21; positron emission tomography; diffuse large B-cell lymphoma; biomarker
Received: July 27, 2018 Accepted: September 08, 2018 Published: October 05, 2018
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.
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