The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential

Abstract

In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal fistromal cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.

Comprehensive analysis of the ability of the Cuproptosis- related gene signature to predict the prognosis of patients with pediatric acute myeloid leukemia

“…Then, we assessed the association between the cuproptosis risk score and immune cell abundance. The results showed that the risk score was positively correlated with activated and effector memory CD4 T cells, memory B cells, and follicular helper T cells but negatively correlated with activated NK and resting CD4 + memory T cells, both of which are known for their pivotal roles in the antitumor immune response 37 . Studies have reported that patients with high memory T-cell activation have shorter OS, whereas those with high memory T-cell quiescence have longer OS 38 .…”

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia

“…The abundance of infiltration of tumor immune cells also differed between the high- and low-risk groups. Compared to the high-risk group, resting CD4 + memory T cells and follicular helper T cells, both of which were well acknowledged to exert an important antitumor immune response ( Watanabe, 2021 ), infiltrated at higher levels in the low-risk group; whereas tumorigenesis-, angiogenesis- and immune suppressing-related cell types, such as M2 macrophages, monocytes, antigen-presenting cells, and dendritic cells ( Nahas et al, 2019 ; Fu and Song, 2021 ), showed higher infiltration levels in the high-risk group. Furthermore, this study also found that patients with high-risk scores showed a worse prognosis than those with low-risk scores.…”

Panel Sequencing of Primary Cutaneous B-Cell Lymphoma

“…Functional loss of TNFRSF14 is implicated in orchestrating the composition of the immune environment via the ligation of the B- and T-lymphocyte attenuator (BTLA) and regulating the expression of stroma-derived cytokines [ 42 ]. These genetic events may thus contribute to the dense infiltration of tumor-associated immune cells, as observed histologically in PCFBCL.…”