Unveiling the Role of the Tumor Microenvironment in the Treatment of Follicular Lymphoma

Abstract

Follicular lymphomas (FL) are neoplasms that resemble normal germinal center (GC) B-cells. Normal GC and neoplastic follicles contain non-neoplastic cells such as T-cells, follicular dendritic cells, cancer associated fibroblasts, and macrophages, which define the tumor microenvironment (TME), which itself is an essential factor in tumor cell survival. The main characteristics of the TME in FL are an increased number of follicular regulatory T-cells (T_reg) and follicular helper T-cells (T_fh), M2-polarization of macrophages, and the development of a nodular network by stromal cells that creates a suitable niche for tumor growth. All of them play important roles in tumor angiogenesis, inhibition of apoptosis, and immune evasion, which are key factors in tumor progression and transformation risk. Based on these findings, novel therapies have been developed to target specific mutations present in the TME cells, restore immune suppression, and modulate TME.

Keywords: follicular lymphoma; therapeutic targets; tumor microenvironment.

Figure 1

A roadmap of various drugs directed against follicular lymphoma (FL). Therapies against FL cells include anti-CD20 monoclonal antibodies (mAbs), CAR-T-cells, immunomodulatory drugs, PI3K inhibitors, Bruton’s tyrosine-kinase inhibitors, and epigenetic regulators, which can also influence the surrounding microenvironment. Regarding the TME, therapies against cells with pro-tumor activity include immune checkpoint inhibitors, anti-CSF-1, and anti-CD47. These drugs aim to block different targets expressed in T-cells (Treg, Tfh, and Tfr) and macrophages, thus stimulating the immune response. Therapies directed toward TME cells with anti-tumor activity include anti-CD137 and anti-CD40 mAbs (immune checkpoint activators), bispecific molecules, anti-LAG3/TIGIT + anti-PD-1/PD-L1 therapy, and lenalidomide.