Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

Abstract

Follicular Lymphoma (FL), the most common indolent non-Hodgkin's B cell lymphoma, is a paradigm of the immune microenvironment's contribution to disease onset, progression, and heterogeneity. Over the last few years, state-of-the-art technologies, including whole-exome sequencing, single-cell RNA sequencing, and mass cytometry, have precisely dissected the specific cellular phenotypes present in the FL microenvironment network and their role in the disease. In this already complex picture, the presence of recurring mutations, including KMT2D, CREBBP, EZH2, and TNFRSF14, have a prominent contributory role, with some of them finely tuning this exquisite dependence of FL on its microenvironment. This precise characterization of the enemy (FL) and its allies (microenvironment) has paved the way for the development of novel therapies aimed at dismantling this contact network, weakening tumor cell support, and reactivating the host's immune response against the tumor. In this review, we will describe the main microenvironment actors, together with the current and future therapeutic approaches targeting them.

Keywords: follicular lymphoma; immunotherapy; microenvironment.

Figure 1

An integrative view of follicular lymphoma (FL) microenvironment and its crosstalk with genetic drivers. (A) FL is highly infiltrated with several T cell subpopulations, where T_FH are fundamental players through MHC II and CD40L, while immunosuppressive T_REG hamper cytotoxic T cells (CTLs) activation. Fibroblastic reticular cells (FRCs) also participate in immunosuppression by secreting extracellular matrix (ECM) proteins that regulate T cell trafficking and cooperate with T_FH. (B) FL cells favor the recruitment of monocytes through CCL2 and CSF-1 that differentiate and polarize mostly into M2-like macrophages expressing PD-L1 and PD-L2 and dampening CTLs cytotoxic activity. Both macrophages and FDCs activate B cell receptors (BCRs) through lectins binding to mannosylated BCR. Likewise, FDCs also activate BCRs through the presentation of immunocomplexes to FL cells. Neutrophils are recruited through IL8 secretion in the FL niche and support lymphoma growth. (C) Several genetic alterations corrupt the microenvironment to better support FL. Mutations in CREBBP and deletions in B2M genes reduce MHC II and MHC I expression, respectively. On the contrary, aberrant CATHEPSIN B leads to an increase in MHC II expression and CD8 expansion. Both EZH2 and RRAGC mutations reduce the need for T_FH help making FL cells more dependent on FDCs, while disruption of the HVEM–BTLA axis allows uncontrolled T_FH support to FL cells.