Follicular Lymphoma B Cells Generate Functional Regulatory T Cells Via ICOS/ICOSL Pathway and Are Inhibited By Intratumoral Tregs

The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor infiltrating regulatory T cells (Tregs). The mechanism of Tregs 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 (n = 20), diffuse large B cell lymphoma (DLBCL; n = 10), classical Hodgkin lymphoma (cHL; n = 9) and reactive lymphadenitis (rL; n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25^high CD127^low/- Tregs in FL tissues. These Tregs comprised activated ICOS⁺ Tregs which were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25^high Foxp3^high Tregs expressing ICOS. Tregs generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interaction between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. These data highlight the role of Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy in FL