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 stem 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.
Highlights
A variety of treatment strategies for follicular lymphoma (FL) are currently used in the clinic, including observation without any treatment, rituximab alone, the anticluster of differentiation (CD)20 antibody combined with monotherapy or a combination of chemotherapy, radiotherapy in the case of limited disease, radioimmunotherapy, and high-dose chemotherapy followed by hematopoietic stem cell transplantation
As for T cells, intratumoral T cells in FL lymph node (LN) are has been suggested to abolish the negative effect of CD163+ tumor-associated macrophages heterogeneous depending on the prevalence of various T-cell subpopulations and location (TAMs) [4]
T-follicular regulatory cells (TFRs) originate from naïve Tregs that upregulate B-cell lymphoma 6 (BCL6) upon activation, leading to CXCR5 expression that direct TFRs to the germinal center (GC) through gradients of CXCL13 [10,11,12]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. As for T cells, intratumoral T cells in FL LNs are has been suggested to abolish the negative effect of CD163+ tumor-associated macrophages heterogeneous depending on the prevalence of various T-cell subpopulations and location (TAMs) [4]. Patients with intrafollicular or on the prevalence of various T-cell subpopulations and location of the cells in relation perifollicular (in a follicular pattern) forkhead box protein 3 (FoxP3)+ cells have a to the follicles. Patients with intrafollicular or perifollicular (in a follicular significantly higher risk of histologic transformation and shorter survival than those with pattern)+ forkhead box protein 3 (FoxP3)+ cells have a significantly higher risk of histologic. High numbers of tumor-infiltrating FoxP3+ cells are related to Programmed cell death-1 (PD-1) is a well-known T-cell exhaustion marker, but two improved overall survival (OS) in FL [6]. Thermore, T cells infiltrated in the FL LN are not exhausted, and there are other reasons contributing to their tolerogenic function
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