Abstract
Simple SummaryTie2-expressing monocytes (TEM) characterized by the phenotype of CD14+CD16+Tie2+ are seen as the new immunosuppressive force in tumors. However, little is known about the role of circulating TEM in chronic lymphocytic leukemia (CLL) as opposed to their role in solid tumors. In the current study, we observed an increased percentage of TEMs in CLL patients. A greater than 14.82% proportion of TEM foretells an unfavorable prognosis. This threshold has predicted a shorter time from diagnosis to therapy, and worse overall survival. Despite these results, a multivariable Cox regression model performed in 104 CLL patients did not identify TEM as an independent predictor of survival. However, TEM, as an important element of the tumor-microenvironment, can be an important complement to other prognostic indicators.Tie2-expressing monocytes (TEMs) are associated with tumor progression and metastasis. This unique subset of monocytes has been identified as a potential prognostic marker in several solid tumors. However, TEMs remain poorly characterized in hematological cancers, including chronic lymphocytic leukemia (CLL). This study analyzed, for the first time, the clinical significance of TEM population in CLL patients. Flow cytometry analysis of TEMs (defined as CD14+CD16+Tie2+ cells) was performed at the time of diagnosis on peripheral blood mononuclear cells from 104 untreated CLL patients. Our results revealed an expansion of circulating TEM in CLL patients. These monocytes express high levels of VEGF and suppressive IL-10. A high percentage of TEM was associated closely with unfavorable prognostic markers (ZAP-70, CD38, 17p and 11q deletion, and IGHV mutational status). Moreover, increased percentages of circulating TEMs were significantly higher in patients not responding to the first-line therapy as compared to responding patients, suggesting its potential predictive value. High TEM percentage was also correlated with shorter overall survival (OS) and shorter time to treatment (TTT). Importantly, based on multivariate Cox regression analysis, TEM percentage was an independent predictor for TTT. Thus, we can suggest the adverse role of TEMs in CLL.
Highlights
Numerous studies have shown that peripheral blood monocytes are a heterogeneous cell population [1,2,3]
Clinical stages were determined according to the Rai classification system [19]: 43 patients were at Stage 0, 32 patients were at Stage I, 15 patients were at Stage II, 8 patients were at Stage III and 6 patients were at Stage IV
Flow cytometry analysis was used for the identification of circulating Tie2-expressing monocytes (TEMs) in the chronic lymphocytic leukemia (CLL) patients (Figure 1a–f)
Summary
Numerous studies have shown that peripheral blood monocytes are a heterogeneous cell population [1,2,3]. The TEM population represents 2 to 7% of blood mononuclear cells (about 20% of a monocytic population) [4,5]. It is known that the abundance and activity of Tie2-positive monocytes are directly dependent on angiopoietin-2 (Ang2) [7,10,11]. TEMs migrate to Ang-2, released by activated endothelial cells and newly formed vessels within a tumor, which is suggested by a mechanism of TEMs targeting tumor tissue [4]. Some reports indicate that Tie expression monocytes increase the formation of regulatory T cells (Treg). It is believed that this is directly related to IL-10 activity, anti-inflammatory cytokines released by this monocyte subpopulation [7,10,14]
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