Abstract
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.
Highlights
Follicular lymphoma (FL) is a low-grade B cell lymphoma usually characterized by long life expectancy and heterogeneous outcome
Foxp3+ cells did not co-expressed follicular helper T-cell markers and were 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
Altered ratios between B-cells and other immune cells in follicular lymphoma (FL) compared to reactive lymph nodes (rLN) would drive evident modifications of the level of molecules shared with lymphoma cells
Summary
Follicular lymphoma (FL) is a low-grade B cell lymphoma usually characterized by long life expectancy and heterogeneous outcome. About one third of FL patients alternate periods of disease remission with recurrent relapses. Some FLs undergo histologic transformation to a high-grade neoplasm, a transition associated with a more aggressive clinical course and poor survival [1]. The current evaluation of the risk of relapse/ resistance to multiagent chemotherapy of FL is based on clinical parameters summarized in the Follicular Lymphoma www.oncotarget.com. International Prognostic Index (FLIPI) while no consistent biological marker has been identified that predicts the survival or the risk of relapse after drug treatments [2]. The new discovered somatic mutations are promising markers of prognosis in FL, to date no single hallmark or single driver mutation can be considered predictive of relapse
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