Data from Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy

Abstract

<div>Abstract<p>The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (<i>n</i> = 20), diffuse large B-cell lymphoma (<i>n</i> = 10), classical Hodgkin lymphoma (<i>n</i> = 9), and reactive lymphadenitis (<i>n</i> = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25<sup>high</sup>CD127<sup>low/neg</sup> Tregs in FL tissues. These Tregs comprised activated ICOS<sup>+</sup> Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL <i>in vitro</i> and to generate CD25<sup>high</sup>FoxP3<sup>high</sup> Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. <i>Cancer Res; 76(16); 4648–60. ©2016 AACR</i>.</p></div>