Abstract
Simple SummaryFollicular lymphoma is a paradigm of tumors that require the interaction between tumor and microenvironment cells to foster their development from initial steps to progression. Recent large-scale genome studies have uncovered multiple genetic alterations that cooperate with the lymphoma microenvironment to promote cell survival, proliferation and to facilitate tumor evasion from host immune system. Understanding the crosstalk between tumor B-cells and the microenvironment is fundamental to identify vulnerabilities that may offer novel therapeutic targets. This review highlights recent findings showing the effect of common genetic mutations modulating the cell composition and phenotype of the tumor microenvironment and the novel therapeutic perspectives to target these interactions. 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.
Highlights
We have recently demonstrated that Follicular Lymphoma (FL)-follicular dendritic cells (FDCs) niche promotes, via the secretion of CCL2 and colony-stimulating factor-1 (CSF-1), monocyte recruitment, differentiation, and polarization towards an M2-like pro-tumoral phenotype, as seen in FL patient biopsies [5], favoring angiogenesis, dissemination, and immunosuppression [22]
Further trials in FL confirmed these values (57% overall response rate (ORR), 6% CR) [59], demonstrating that PI3Kδ inhibition has significant efficacy in FL, it has serious side effects, mainly severe diarrhea, hepatotoxicity, or pneumonitis, and, in some cases, made it necessary to stop the treatment [99].PI3Kδ is a key regulator of T follicular helpers (TFH) differentiation [100] and has deleterious effects on T regulatory cells (TREG) [101], which closely relates with some side effects described for this drug and may be responsible for its therapeutic activity
The results demonstrated that the CSF-1R+ cell population only partially overlapped with the M2-type macrophages detected by CD163 expression, in agreement with previous observations about monocyte differentiation, where the CSF-1R gene was not significantly differentially expressed between M1 versus M2 monocyte activation models [136]
Summary
Follicular lymphoma (FL), the most common indolent non-Hodgkin’s lymphoma (NHL), is a biologically heterogeneous disease with clinical variations in patient outcome [1]. FRCs are stromal cells present in the T cell zone of the LN that are endowed with functions that create a permissive niche by secreting components of the extracellular matrix (ECM), including laminin, fibronectin, and collagen IV They organize and regulate immune cell trafficking, differentiation, and migration of T cells through an IL-4/CXCL12 communication axis with TFH , among other signals, and secretion of additional chemokines such as CCL19 and CCL21. We have recently demonstrated that FL-FDC niche promotes, via the secretion of CCL2 and CSF-1, monocyte recruitment, differentiation, and polarization towards an M2-like pro-tumoral phenotype, as seen in FL patient biopsies [5], favoring angiogenesis, dissemination, and immunosuppression [22].
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