CD1d expression is higher in chronic lymphocytic leukemia patients with unfavorable prognosis
Introduction
CD1 molecules are a family of highly conserved antigen presenting proteins that are similar in function to classic major histocompatibility complex (MHC) molecules [1]. In humans, there are five members of the CD1 family (CD1a to e). Of these molecules, CD1d has been the subject of much interest following the finding that the molecule presents glycolipid antigens to a specialized subset of T cells known as natural killer T cells (NKT). The best characterized CD1d-restricted NKT cells in humans are the invariant NKT (iNKT, Valpha24+ NKT) cells, also known as type I NKT cells [2].
CD1d is expressed on normal monocytic-lineage cells (monocytes, macrophages, dendritic cells), on a proportion of B lymphocytes and immature cortical thymocytes. In humans, B lymphocytes expressing CD1d are found in peripheral blood (PB) and in the mantle zone of secondary lymphoid follicles [3], [4], [5]. Moreover, certain tumour types are known to express CD1d molecules. CD1d is detected on the majority of leukaemia cells in patients with acute myeloid leukaemia (AML) [4]. CD1d expression has also been established on tumour cells in patients with B-cell malignancies such as B-cell precursor acute lymphoblastic leukaemia [3] and chronic lymphocytic leukaemia [6], [7]. Recent studies of CD1d expression in human lymphomas showed that CD1d is expressed on the surface of Hodgkin and Red-Stenberg cells in a half of classical Hodgkin lymphoma (cHL) cases. On the other hand, among non-Hodgkin lymphoma (NHL) patients, only 23% of cases are CD1d positive [8].
The functional consequences of CD1d expression on tumour cells are not well understood. However, increasing evidence suggests they may affect iNKT cells [9]. The authors demonstrate that CD1d expression on malignant cells target them for iNKT-mediated killing and there is a direct correlation between downregulation of CD1d expression on tumour cells and cancer progression [10]. The exact mechanisms of iNKT-mediated antitumor immunity have not yet been completely explained. However, iNKT cells are known to have both direct and indirect effector functions, including the capability to activate both innate NK and adaptive T cell-mediated antitumor immunity [10]. Activated iNKT cells have been established to have a direct cytotoxic effect on CD1d-bearing tumour cells in a CD1d-dependent manner. A direct correlation between tumour CD1d expression and their sensitivity to iNKT-mediated antitumor immunity has also been found [4], [10], [11]. It has been previously reported that in patients with chronic lymphocytic leukaemia (CLL), CD1d is expressed on leukemic B cells and mediates antigen presentation to NKT cells [6]. Nevertheless, little is known about the role of CD1d expression in the pathogenesis and clinical course of CLL.
CLL is characterized by a very heterogeneous clinical course, which is slow and indolent in most of the patients, however some patients experience rapid disease progression and anticancer therapy is required shortly after the diagnosis. Many issues in CLL development and progression are still unclear. The role of CD1d expression in CLL immunopathogenesis remains undefined. In this study, we investigated the potential role of CD1d in CLL by analyzing the level of CD1d expression on leukemic B cells in peripheral blood in correlation with clinical and laboratory parameters characterizing disease activity and patients’ immune status.
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Patients and samples
Peripheral blood (PB) samples were obtained from 120 consecutive patients diagnosed with CLL in the Department of Hematooncology and Bone Marrow of Medical University of Lublin between 2002 and 2012 (50 women and 70 men, aged from 38 to 83 years, median age of 66 years). Diagnosis of CLL was based on criteria from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) [12]. Clinical stage was determined according to the Rai classification system [13] as follows: stage 0 (34 cases),
Membrane CD1d expression on B cells from CLL patients and normal subjects
Representative plots from three CLL patients and three healthy donors with different membrane CD1d expression are shown in Fig. 1C. We found significantly lower median percentage of CD1d-positive B cells in CLL patients than in healthy volunteers (p = 0.0001) (Table 2). Likewise, when we compared the level of membrane CD1d expression determined by MFI on B cells from CLL patients and healthy volunteers, we found significant difference between the groups (p = 0.046) (Table 2).
The percentage of
Discussion
CD1d is a MHC class I-like glycoprotein that presents phospholipids and glycolipids to iNKT cells. A variety of tumour cell types express CD1d on the surface, particularly those of hematopoietic origin [4]. In the present study, the expression of CD1d in CLL cells has been investigated. Measuring CD1d expression by flow cytometry and qRT-PCR, we showed lower CD1d molecule and CD1d mRNA expression in CLL patients than in healthy controls. By contrast, another research group reported a
Funding
This work was supported by research grant: N N402 439139 and N N402 351438 from State Funds for Scientific Research National Science Centre (NCN). I-FISH analysis was supported by research grant N N402 683140 from NCN.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
None of the authors declared any conflict of interest.
Acknowledgements
We would like to thank Ms. Monika Pieczykolan and Karolina Olszewska-Bożek for their excellent technical support in this study.
Contributors: Conceived and designed the experiments: ABJ IH. Performed the experiments: ABJ SC JW PC. Performed analysis and interpretation of data: ABJ SC IH. Contributed materials and collected clinical data: WT JW IH. Wrote the paper: ABJ. Critically revised the intellectual content of the manuscript: JR LP. Approved the final version of the manuscript: ABJ IH SC JW
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