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

Abstract

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.

Microenvironment Cell Contribution to Lymphoma Immunity

“…However, the exact role of T FH cells in the context of lymphoma is not fully understood. Part of the difficulty rests in the fact that they can elicit various cytokine-mediated functions simultaneously and can, in turn, be influenced by their microenvironment ( 58 ).…”

An integrative microenvironment approach for follicular lymphoma: roles of inflammatory cell subsets and immune-response polymorphisms on disease clinical course

“…This cluster also presented with elevated expression of TGFBR1, IL-17A, and IL-17F. These results suggest that the quantities of the inflammatory cells, including T-cells, are important when they interact with each other and with cytokines, which reflects the complexity of TME in FL [27]. The mechanisms of these interactions should be explored further in future studies.…”

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

“…Finally, although Tfh and Tfh-like populations have been associated with poor prognosis in lymphoma ( 256 , 257 ) and ICI-treated melanoma ( 258 ), numerous pre-clinical and clinical studies revealed their positive impact on the outcome of many solid tumors ( 259 ), including breast cancer ( 260 , 261 ), non-small-cell lung cancer (NSCLC) ( 262 ), ovarian cancer ( 263 ), and colorectal cancer ( 25 , 26 ). Mechanisms underlying the protective role of Tfh cells are not fully understood, although some evidence point to cooperation with CD8 + T cells and IL-21 ( 25 , 43 ).…”