T follicular helper cells: a potential therapeutic target in follicular lymphoma

Follicular lymphoma (FL), the most common indolent B-cell non-Hodgkin lymphoma (B-NHL), is a germinal center (GC)-derived lymphoma. The mechanisms underlying B-cell differentiation/maturation in GCs could be also involved in their malignant transformation. Moreover, the non-malignant cell composition and architecture of the tumor microenvironment can influence FL development and outcome. Here, we review recent research advances on CD4 helper T cells in FL that highlight the pivotal role of T follicular helper (TFH) cells in a complex multicellular system where they interact with B cells during GC dynamics. After describing the mechanism of FL lymphomagenesis, we discuss the emerging evidence about TFH cell enrichment and involvement in FL tumorigenesis and in B-T cell interaction, TFH regulation by T follicular regulatory cells (TFR) and its potential effect on FL. Then, we provide an overview on the flexible interplay between the different CD4 T-cell subtypes and how this may be predicted in normal and pathologic contexts, according to the cell epigenetic state. Finally, we highlight the importance of targeting TFH cells in the clinic, summarize the main outstanding questions about TFH and TFR cells in FL, and describe strategies to potentiate FL therapy by taking into account TFH cells.