Circulating classical CD14++CD16− monocytes predict shorter time to initial treatment in chronic lymphocytic leukemia patients: Differential effects of immune chemotherapy on monocyte-related membrane and soluble forms of CD163

Abstract

Three main monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++, differentially regulate tumor growth and survival. Thereby, in the present study we aimed to determine the role of distinct monocyte subsets in the prognostication of chronic lymphocytic leukemia (CLL). Moreover, we set out to analyze the effects of standard immune chemotherapy on different monocyte subsets and levels of membrane-associated and soluble forms of CD163, a monocyte/macrophage-related immunomodulatory protein. We demonstrated that the number of peripheral blood classical CD14++CD16- monocytes assessed at the time of diagnosis was negatively correlated with lymphocytosis and was decreased in the CLL patients who required immediate treatment as opposed to patients who qualified to 'watch and wait' strategy. Notably, lower baseline levels of classical CD14++CD16- monocytes in CLL patients who were qualified for 'watch and wait' therapy were associated with shorter time to initial treatment. Notably, therapy with rituximab, cyclophosphamide and fludarabine resulted in a significant reduction in the number of non-classical CD14+CD16++ monocytes and soluble form of CD163 but upregulation of membrane-associated monocyte CD163. Our data indicate that distinct monocyte subsets and two forms of CD163 are differentially modulated by both CLL and immune chemotherapy. Moreover, we proposed that quantification of classical monocytes at the time of diagnosis contributes to better prognostication of CLL patients.

Expression of CD163 and HLA-DR molecules on the monocytes in chronic lymphocytic leukemia patients

“…The differences relate to, among others, the degree of expression of HLA-DR, CD86 and CD1d, which determine their ability to present antigens [8]. Furthermore, the CD14 ++ CD16 + intermediate monocytes have a high expression of CD163 molecule [14] that inhibits activation and proliferation of T cells [27]. It is also a specific marker of monocytes/macrophages exhibiting strong anti-inflammatory properties [28].…”

“…It is currently believed that the CD163 protein is involved in the uptake of the hemoglobin-haptoglobin complex and the regulation of inflammatory processes [12,13]. CD163 may also be in a soluble form (soluble CD163, sCD163) [14]. The role of the sCD163 molecule has not been exactly explained.…”

“…Its higher level was found in hematological cancers, including chronic lymphocytic leukemia [15]. Moreover, CD163 is certainly a marker of macrophage activity and is generally thought to be associated with downregulation of inflammation, but its biological role still has not been fully elucidated [14,15]. Monocytes are one of the least known immune cells with a potentially important role in the pathogenesis of CLL.…”

Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks

“…Because our multivariate analysis revealed a significant relationship between the activation of immune cells and disease course, we explored their prognostic value. We showed [33,34]. Regarding monocytes and monocyte-derived cells in CLL, there is already evidence that they promote CLL cell survival and proliferation [34], and have deregulated genes involved in phagocytosis and inflammation [12].…”

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukemia using patient similarity networks

“…In particular, a high percentage of intermediate monocytes (> 5.4%) was prognostic for progressive disease and these patients have 2.5-fold higher likelihood of event than those with low percentage of intermediate monocytes, irrespective of the treatment. The importance of monocytes for the prognosis of CLL patients has been demonstrated in recent studies showing association of monocyte counts, particularly of circulating classical monocytes, with time to the rst therapy, aggressiveness and disease outcome [33,34]. Regarding monocytes and monocyte-derived cells in CLL, there is already evidence that they promote CLL cell survival and proliferation [34], and have deregulated genes involved in phagocytosis and in ammation [12].…”