Abstract
Recently, systemic administration of a human monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expressed on circulating T cells in patients with chronic lymphocytic leukaemia (CLL) has been considered. Also, CLL cells have been shown to express CTLA-4, increased levels of which in the leukaemic compartment are a predictor of good clinical outcome. Since both CLL and Treg microenvironment cells can be targeted by the CTLA-4 blocking antibody in this immunotherapy approach, the investigation of the functional effect of CTLA-4 blockade on CLL cells might be of potential clinical relevance. The main aim of this study was to examine the effect of CTLA-4 blockade on proliferation activity and apoptosis of CLL cells in patients with low and high CTLA-4 expression. We found that in the high CTLA-4-expressing CLL group, CTLA-4 blockade on the CLL cell surface resulted in a significant increase in the median percentages of Ki67+ cells and a tendency to decrease in the proportion of apoptotic cells. In contrast, in the low CTLA-4 expressors, CTLA-4 blockade did not affect the proliferation activity or the frequency of apoptosis. This study reports for the first time the different effect of CTLA-4 blockade on CLL cells in CLL patients depending on the levels of CTLA-4 expression. CTLA-4 blockade seems to induce pro-survival signals in leukaemic cells from CLL patients exhibiting high CTLA-4 expression, suggesting that an immunotherapy approach based on the systemic use of monoclonal anti-CTLA-4 antibodies could be an unfavourable strategy for some CLL patients.
Highlights
Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia recognised in North America, Europe and Australasia, accounting for about one third of all cases of adult leukaemia [1,2,3]
Since cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is known as an anti-proliferative factor [12, 13, 28], we examined whether freshly drawn CLL cells from the two studied groups of CLL patients differ regarding the proliferation activity; the expression of Ki67 protein in CLL cells was estimated
As CTLA-4 is involved in the regulation of cell survival [21, 29], we investigated whether freshly drawn CLL cells from the two studied groups of CLL patients differ in terms of the apoptosis rate
Summary
Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia recognised in North America, Europe and Australasia, accounting for about one third of all cases of adult leukaemia [1,2,3]. It is a disease of senior age, since the median age at diagnosis is close to 70 years [2]. The disease progresses quickly toward more advanced stages [10, 11] These patients require early therapy and die relatively rapidly despite
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