Patients with chronic lymphocytic leukaemia (CLL) differ in the pattern of CTLA-4 expression on CLL cells: the possible implications for immunotherapy with CTLA-4 blocking antibody

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.

Frequency and functional characterization of exhausted CD8+ T cells in chronic lymphocytic leukemia

“…Chronic lymphocytic leukemia (CLL) displays significant clinical heterogeneity, as in some patients, the disease remains stable for many years or develops very slowly, whereas in others, the disease progresses quickly toward more advanced stages . Cell‐mediated immunity play major roles in effective anti‐tumor immune responses controlling the tumor growth and proliferation, but T cell responses are modulated and regulated by the tumor microenvironments and thus finally fail to eradicate the tumor cells .…”

“…Chronic lymphocytic leukemia (CLL) displays significant clinical heterogeneity, as in some patients, the disease remains stable for many years or develops very slowly, whereas in others, the disease progresses quickly toward more advanced stages. [1][2][3] Cell-mediated immunity play major roles in effective anti-tumor immune responses controlling the tumor growth and proliferation, but T cell responses are modulated and regulated by the tumor microenvironments and thus finally fail to eradicate the tumor cells. 4 Attention has recently been focused on a subset of T cells named "Exhausted T cells" which could be originated from both T-CD4 + and T-CD8 + lymphocytes and are considered to play a key role in regulation and suppression of host immune responses during chronic infections and cancers.…”

PD-1 overexpression determines the disproportion of circulating Th1/Th17/Treg cells and clinical outcome of multiple myeloma

“…It is well established that immune checkpoint receptors play an essential role in the immune surveillance and anti-tumor response [5]. We and others have previously demonstrated the dysregulated expression of CTLA-4, PD-1, and BTLA suppressors in tumors [4,[14][15][16][17][18][19][20][21][22]. We also reported that CTLA-4 blocking antibody might be a beneficial form of immunotherapy for a proportion of chronic lymphocytic leukemia (CLL) patients depending on the level of CTLA-4 expression on leukemic cells; for those with high CTLA-4 expression, it could be an unfavorable strategy leading to induction of pro-survival signals in CLL cells [18].…”

“…There is growing body of evidence, including ours, that alterations in the immune checkpoints' expression in T cells affect the clinical outcome of cancer [4,14,16,[18][19][20][21][22]. Therefore, we wanted to find out whether the dysregulated expression of T cell inhibitors in MM might be associated with clinicopathologic features, such as albumin and beta2-microglobulin level, myeloma isotype, PLC numbers in the BM, light chain, renal function, and tumor stage.…”

Cancer immunotherapy in mice and humans: personal observations*

“…This should lead to better recognition of altered, mutated cells, allowing them to be more efficiently removed. This works for a period of time, but is then blocked by the expression of checkpoint blockers on activated lymphocytes [38][39][40][41]. In B-CLL, it can thus be proposed that complex associated active immunotherapy be used in conjunction with passive immunotherapy (rituximab), followed by antibodies that block the checkpoint blockers -e.g., directed at CTLA4 (ipilimumab) or PD-1 and its ligands [42,43].…”