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Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the peripheral accumulation of neoplastic B cells and is frequently complicated by the systemic immunosuppression associated with an impairment in B and T lymphocyte activation. We hypothesized that the expression of immune checkpoint suppressors B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen (CTLA-4) is disturbed in both lymphocyte subpopulations in CLL. The expression of CTLA-4 and BTLA mRNA was determined by real-time PCR, while CTLA-4 protein expression (surface or intracellular) was estimated in BTLA+ lymphocytes by flow cytometry. In CLL patients, we observed a higher gene transcript level of BTLA and CTLA-4 than in healthy individuals in both freshly isolated and PMA stimulated B and T cells. Remarkably, lower amounts of both inhibitory proteins were found in peripheral blood (PB) CLL B cells, whereas normal BTLA and elevated CTLA-4 were found in T cells. Consistently, there was a prevalence of CTLA-4+ cells within circulating BTLA+ T cells cells of patients confronting PB healthy cells. After in vitro stimulation, the only change found in CLL patients was a decrease in BTLA expression in B and T lymphocytes. In contrast, healthy lymphocytes responded more vigorously as regards the BTLA and CTLA expression with substantially higher frequency of CD69+ cells under the stimulating condition compared to corresponding cells from the CLL group. Our results indicate that CLL development is associated with the affected expression of BTLA and CTLA-4 checkpoint receptors in PB and its impaired expression might be associated with lowering of the threshold for B cell activation and proliferation, while upregulated CTLA-4 expression in CLL peripheral BTLA+ T cells may contribute to suppressed T cell effector functions. This hypothesis needs to be validated in future studies, which would allow us to explain how the increased or decreased expression of these molecules affects the cell function.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in western countries and is characterized by the gradual accumulation of mature B lineage-specific markers such as CD19, CD20, and CD23 and the CD5 antigen in lymphoid tissues, bone marrow, and peripheral blood (PB)
We noticed that B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen 4 (CTLA-4) gene polymorphisms are associated with mRNA expression and that variations in their genes might be considered as potential CLL risk factors [21, 22]
Development does affect BTLA and CTLA-4 suppressor expression at both the mRNA and the protein level in circulating B and T cells involved in systemic immunosuppression in CLL
Summary
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in western countries and is characterized by the gradual accumulation of mature B lineage-specific markers such as CD19, CD20, and CD23 and the CD5 antigen in lymphoid tissues, bone marrow, and peripheral blood (PB). The discovery that malignant cells can evade the host immune systems by inhibiting T cells focused the attention on new therapeutic targets in cancer therapy—immune. The increased expression of the cytotoxic T lymphocyte antigen 4 (CTLA-4) molecule was found in the T cell compartment in CLL patients [2,3,4]. CTLA-4 blockade was associated with potent T cell proliferation in response to autologous and allogeneic CLL B cells, suggesting that this approach could represent a therapeutic opportunity to enhance an immune response against leukemia cells. As was shown by us and others, CTLA4 protein expression in peripheral CLL cells is higher than that in normal B lymphocytes and positively correlates with better outcomes for CLL patients [5,6,7,8]. For “high CTLA-4 expressed patients,” this approach induces prosurvival signals and is an unfavourable strategy for these patients, while patients with low CTLA-4 expression might benefit from CTLA-4 blocking therapy [8]
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