Several studies have demonstrated impaired immune cell functions in chronic lymphocytic leukemia (CLL) patients, contributing to tumor evasion and disease progression. However, in CLL-like monoclonal B cell lymphocytosis (MBL) studies are scarce. Herein, we characterized the immune environment in 62 individuals with clinical MBL, 56 early stage CLL patients and 31 healthy controls. Gene expression arrays and qRT-PCR were performed on RNA from CD4 peripheral blood cells; serum cytokines were measured by immunoassays; and HLA-DR expression on circulating monocytes as well as Th1, cytotoxic, exhausted and effector CD4 T cells were characterized by flow cytometry. Besides, cell cultures of clonal B cells and CD14-enriched or depleted cell fractions were performed. Strikingly, MBL and early stage CLL differed in proinflammatory signatures. An increased inflammatory drive mainly orchestrated by monocytes was identified in MBL, which exhibited enhanced phagocytosis, pattern recognition receptors, IL8, HMGB1 and acute response signaling pathways, and increased proinflammatory cytokines (in particular IL8, IFNγ and TNFα). This inflammatory signature was diminished in early stage CLL (reduced IL8 and IFNγ levels, IL8 signaling pathway and monocytic HLA-DR expression compared to MBL), especially in those patients with mutations in IGHV genes. Additionally, CD4 T cells of MBL and early stage CLL showed a similar upregulation of Th1 and cytotoxic genes, and expanded CXCR3 and perforin CD4 T cells as well as PD1 CD4 T cells compared to controls. Cell culture assays disclosed tumor-supporting effects of monocytes similarly observed in MBL and early stage CLL. These novel findings reveal differences in the inflammatory environment between MBL and CLL, highlighting an active role for antigen stimulation in the very early stages of the disease, potentially related to malignant B cell transformation.
Copyright © 2021. Published by Elsevier Inc.

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