ABSTRACT: Several studies have demonstrated an impaired function of the microenvironment in chronic lymphocytic leukemia (CLL), contributing to immune evasion of tumor cells and disease progression. However, in CLL-like monoclonal B cell lymphocytosis (MBL) studies are scarce. Herein, a comprehensive characterization of the microenvironment in 59 MBL, 56 early stage CLL and 31 healthy controls was conducted. Gene expression arrays and qRT-PCR were performed on RNA from CD4+ peripheral blood cells; serum cytokines were measured by immunoassays and proteomic studies; and flow cytometry was applied to evaluate peripheral blood cytotoxic, Th1, exhausted and effector CD4+ T cells, besides monocytic CD14, CD4 and HLA-DR expression. MBL and early stage CLL showed a similar upregulation of cytotoxic and Th1-related genes, expanded perforin+ and CXCR3+ CD4+ T cells as well as PD1+ CD4+ T cells compared to controls. However, a strong inflammatory response was only identified in MBL: enhanced phagocytosis, pattern recognition receptors, IL8, HMGB1, TREM1 and acute response signaling pathways, along with increased levels of proinflammatory cytokines (remarkably IL8, IFN? and TNF?). Of note, this inflammatory drive was decreased in early stage CLL: diminished proinflammatory cytokines including IFN?, decreased IL8 signaling pathway and lower monocytic HLA-DR expression compared to MBL. Besides, this inflammation was especially reduced in IGHV mutated CLL, involving a decrease of the proinflammatory HMGB1 signaling pathway. These novel findings reveal a different pathophysiology between MBL and CLL, paving the way for the development of pre-emptive immunotherapies with optimal benefits at MBL and early stage CLL, before intense immune exhaustion.
