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Review
. 2018 May 8;8:147.
doi: 10.3389/fonc.2018.00147. eCollection 2018.

The Role of Macrophage/B-Cell Interactions in the Pathophysiology of B-Cell Lymphomas

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Free PMC article
Review

The Role of Macrophage/B-Cell Interactions in the Pathophysiology of B-Cell Lymphomas

Lan V Pham et al. Front Oncol. .
Free PMC article

Abstract

Macrophages (MPs) are heterogeneous, multifunctional, myeloid-derived leukocytes that are part of the innate immune system, playing wide-ranging critical roles in basic biological activities, including maintenance of tissue homeostasis involving clearance of microbial pathogens. Tumor-associated MPs (TAMs) are MPs with defined specific M2 phenotypes now known to play central roles in the pathophysiology of a wide spectrum of malignant neoplasms. Also, TAMs are often intrinsic cellular components of the essential tumor microenvironment (TME). In concert with lymphoid-lineage B and T cells at various developmental stages, TAMs can mediate enhanced tumor progression, often leading to poor clinical prognosis, at least partly through secretion of chemokines, cytokines, and various active proteases shown to stimulate tumor growth, angiogenesis, metastasis, and immunosuppression. Researchers recently showed that TAMs express certain key checkpoint-associated proteins [e.g., programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1)] that appear to be involved in T-cell activation and that these proteins are targets of other specific checkpoint-blocking immunotherapies (anti-PD-1/PD-L1) currently part of new therapeutic paradigms for chemotherapy-resistant neoplasms. Although much is known about the wide spectrum and flexibility of MPs under many normal and neoplastic conditions, relatively little is known about the increasingly important interactions between MPs and B-lymphoid cells, particularly in the TME in patients with aggressive B-cell non-Hodgkin lymphoma (NHL-B). Normal and neoplastic lymphoid and myeloid cell/MP lineages appear to share many primitive cellular characteristics as well as transcriptional factor interactions in human and animal ontogenic studies. Such cells are capable of ectopic transcription factor-induced lineage reprogramming or transdifferentiation from early myeloid/monocytic lineages to later induce B-cell lymphomagenesis in experimental in vivo murine systems. Close cellular interactions between endogenous clonal neoplastic B cells and related aberrant myeloid precursor cells/MPs appear to be important interactive components of aggressive NHL-B that we discuss herein in the larger context of the putative role of B-cell/MP cellular lineage interactions involved in NHL-B pathophysiology during ensuing lymphoma development.

Keywords: B-cell lymphoma; immune suppression mechanism; lymphoma-associated macrophages; macrophages; tumor microenvironment.

Figures

Figure 1
Figure 1
Characterization of lymphoma-associated macrophages (MPs) in B-cell lymphoma cell cultures. (A) Examples of lymphoma cell–tumor-associated MP colony aggregation in culture after 2 weeks. Left, phase-contrast light microscopic image; middle, Wright–Giemsa stain (400×); right, Wright–Giemsa stain (400×). (B) Examples of MP clustering/aggregation in mantle cell lymphoma (MCL) cell culture under hypoxic conditions. Left, phase-contrast light microscopic image; middle, confocal microscopic analysis of CD68+ MPs (red) and CD5+ cells (green); right, hematoxylin and eosin stain (200×). (C) Hematoxylin and eosin and Wright–Giemsa stains showing mitotic figures in MPs in primary MCL culture after 8 weeks under hypoxic conditions (400×).
Figure 2
Figure 2
Hypothetical model of B-cell/MP interactions in B-cell lymphomas. This model predicts that indolent and retransformed or non-transformed lymphoma cells do not initially exhibit autonomous or spontaneous-independent neoplastic cell growth but instead must undergo interactions with indigenous non-neoplastic cells, specifically, monocytes or macrophages (MP)-derived tumor-associated MPs (TAMs) that bind, stimulate, and activate targeted lymphoma cells, to adopt aggressive autonomous phenotypes. The postulated mechanism for this relationship is that a high monocyte count is a surrogate biomarker for the tumor microenvironment, reflecting the functions of immunosuppressive peripheral blood monocytes recruited by lymphoma cells to differentiate monocytes into polarized MPs (M2) that can in turn activate the tumor cells. In addition, the aggregated TAMs (red) can protect tumor cells and, potentially, cancer stem cells (blue) within their clusters from chemotherapy, enabling the tumor cells to survive (residual disease) and re-establish (relapse) at a later time.

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