MicroRNA signatures and Foxp3+ cell count correlate with relapse occurrence in follicular lymphoma
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Giorgio Malpeli1,2, Stefano Barbi2, Corinna Greco3, Simonetta Zupo4, Anna Bertolaso2, Maria Teresa Scupoli5, Mauro Krampera3, Paul Takam Kamga3, Carlo Maria Croce6, Aldo Scarpa2,7 and Alberto Zamò2,8
1Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy
2Department of Diagnostics and Public Health, University of Verona, Verona, Italy
3Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Italy
4Laboratory of Molecular Diagnostics, IRCCS-AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
5Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
6Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
7Applied Research on Cancer-Network, ARC-NET, University of Verona, Verona, Italy
8Department of Oncology, University of Torino, Torino, Italy
Giorgio Malpeli, email: [email protected]
Keywords: follicular lymphoma; relapse; microRNAs; Foxp3; heterogeneity
Received: August 23, 2017 Accepted: January 30, 2018 Published: April 13, 2018
First line drug treatment of follicular lymphoma (FL) patients is followed by a highly variable disease-free time before relapse in about one third of patients. No molecular marker is able to predict efficiently the risk of relapse. We investigated the expression profile of microRNAs (miRNAs) by microarrays and of the tumor microenvironment by immunohistochemistry in 26 FLs and 12 reactive lymph nodes (rLN) as reference. Twenty-nine miRNAs were differentially expressed in FLs compared to rLNs and some of them discriminated grade 1 from 3a FLs. Both FLs and rLNs displayed molecular heterogeneity. FLs grouped into two clusters mostly driven by the tumor T-cell content. Among 21 drug-treated FL patients with an average follow-up of 13.5 years, eight cases relapsed. Twenty-six miRNAs discriminated between relapsed and non-relapsed FLs. Ten miRNAs also correlated with Foxp3+ cells number. Notably, Foxp3+ cells were significantly less in relapsed patients and lower Foxp3+ cell number associated with shorter time-to-relapse. Foxp3+ cells did not co-expressed follicular helper T-cell markers and were therefore classified as regulatory T cells rather than follicular regulatory T-cells. These findings introduce new knowledge about the relationship between miRNA alterations and infiltrating immune cells and show that Foxp3+ cells might be predictive of disease relapse.
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