Abstract
Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western population and it is characterized by a heterogeneous clinical course [1]
Expression of PD1 was found on tumor infiltrating and peripheral T cells in Hodgkin lymphoma, B-cell non-Hodgkin lymphoma as well as in the adult T-cell leukemia [19,20,21,22]
As a novel feature of CLL cells we observed expression of PD-L1, which has not been described in B-cell non-Hodgkin lymphomas to date [22,24,25,26]
Summary
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western population and it is characterized by a heterogeneous clinical course [1]. Mechanisms of CLL pathogenesis are not fully described yet. Emerging data underlines the key role of the B-cell receptor (BCR) in CLL transformation and progression [1]. In CLL cells the BCR is weakly expressed [1,2]. It is noteworthy that several factors involved in BCR signaling have impact on the biology and prognosis of CLL. An aberrant expression of 70 kDa tyrosine kinase zeta-associated protein (ZAP-70), which takes part in the BCR signal transduction pathway, correlates with poor prognosis [3]. Presence of an unmutated gene of the variable regions of the immunoglobulin heavy chain (IGHV) appears in about half of CLL patients and is correlated with an unfavorable prognosis [4].
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