Chronic Lymphocytic Leukemia B Cells Can Express CD40 Ligand and Demonstrate T-Cell Type Costimulatory Capacity

Schattner, Elaine J.; Mascarenhas, John; Reyfman, Inna; Koshy, Mary; Woo, Caroline J.; Friedman, Steven; Crow, Mary K.

doi:10.1182/blood.v91.8.2689.2689_2689_2697

Cited by 73 publications

(37 citation statements)

References 51 publications

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“…Accordingly, CLL cells can express CD154 and furthermore, with T-cell type functional capacity, e.g. induction of antibody production by normal human B cells (7). Although interleukins such as IL-1a, IL-1b, IL-2, IL-6, IL-7, IL-8, IL-10, IL-13, and IFN-c, TNF, GM-CSF and TGF-b have been discussed previously (8,9), their role in the natural history of CLL is still unclear.…”

Section: Discussionmentioning

confidence: 99%

CD8+ chronic lymphocytic leukemia: an extensive characterization of a bizarre hybrid neoplasia

Richaud‐Patin¹,

Piedras²,

Carrillo-Maravilla³

et al. 2003

European J of Haematology

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Atypical chronic lymphocytic leukemia (CLL) expressing the CD8 antigen have a frequency of less than 0.5% of all cases, however, they are not yet been fully characterized. Herein a CD8+ CLL case was extensively studied. Besides the classical CLL antigen expression, an unusual presence of surface markers such as CD11c, CD56, and CD154 was observed. Moreover, gene expression of chemokine receptors belonging to the CCR family were clearly evidenced as well as mRNA for both, Th1 and Th2 cytokines. Likewise, granzyme A, B and perforin gene expression, cytotoxic T cell or NK enzymes were found. The intricate profile of membrane molecules and gene expression suggest that it could be favorable, rather than deletereous, for the maintainance of the neoplastic process.

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Section: Discussionmentioning

confidence: 99%

CD8+ chronic lymphocytic leukemia: an extensive characterization of a bizarre hybrid neoplasia

Richaud‐Patin¹,

Piedras²,

Carrillo-Maravilla³

et al. 2003

European J of Haematology

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“…CD40 is a transmembrane glycoprotein of the tumour necrosis factor receptor superfamily that is involved in B-cell activation, differentiation and the formation of germinal centres (Lee et al, 2003). It is highly expressed in B-cell malignancies, such as MM (Pellat-Deceunynck et al, 1994), chronic lymphocytic leukaemia (Schattner et al, 1998) and NHL (Aggarwal et al, 2009). CD40 activation by its ligand (CD40L) (Armitage et al, 1992) appears to contribute to B-cell tumourigenesis via NFjB, ERK, p38 MAPK and PI3-kinase signalling (Dadgostar et al, 2002).…”

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confidence: 99%

A phase 1 study of lucatumumab, a fully human anti‐CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma

et al. 2012

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SummaryIn this open-label, multicentre, phase 1 study a fully human anti-CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty-eight patients, enrolled using a standard '3 + 3' dose escalation, received one or two (n = 3) cycles of lucatumumab 1Á0, 3Á0, 4Á5 or 6Á0 mg/kg once weekly for 4 weeks. Common lucatumumab-related adverse events were reversible, mild-to-moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n = 1 each). The MTD was 4Á5 mg/kg. At doses ! 3Á0 mg/ kg, sustained receptor occupancy ( ! 87%), observed throughout weekly infusions up to 5 weeks after the last infusion, correlated with an estimated half-life of 4-19 d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for ! 8 months. These findings indicate that single-agent lucatumumab was well tolerated up to 4Á5 mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.

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“…39 Secreted CD40L (sCD40L) can also be produced by CLL cells 18 and in contrast to membrane-bound CD40L, sCD40L alone can induce proliferation only in non-malignant B cells but not in CLL cells. 18 In Figure 4. Activation of downstream signaling by IL4 and sCD40L on CLL cells.…”

Section: Discussionmentioning

confidence: 99%

“…CLL cells, additional signals and/or crosslinking of the CD40 receptor is required. 18,33 In addition, a subset of CLL cells expresses both sCD40L and its receptor, enabling an autocrine loop by which CLL cells can promote their own survival, while non-malignant B cells express only the CD40 receptor. 18,40 In the dose-response of non-malignant B cells to sCD40L, we observed cooperativity which is frequently caused by oligomerization of ligand and/or receptors.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

“…In CLL cells, however, only survival can be induced by sCD40L. 18 In this study, we have compared the responsiveness of CLL cells to different microenvironmental stimuli including treatments with single ligands (also added in combination) T-cell-derived cytokines IL4 and sCD40L were found to be the most efficient factors in rescuing CLL cells from apoptosis in vitro. Although sCD40L when used in vitro is likely to represent physiological secreted CD40L, it cannot be ruledout that observed effects possibly also originate from the physiological functions of membrane-bound CD40L.…”

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Loss of cooperativity of secreted CD40L and increased dose-response to IL4 on CLL cell viability correlates with enhanced activation of NF-kB and STAT6

et al. 2014

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Chronic lymphocytic leukemia (CLL) cells fail to enter apoptosis in vivo as opposed to their non-malignant B-lymphocyte counterparts. The ability of CLL cells to escape apoptosis is highly dependent on their microenvironment. Compared to nonmalignant B cells, CLL cells are more responsive to complex stimuli that can be reproduced in vitro by the addition of cytokines. To understand the molecular mechanism of the environment-dependent anti-apoptotic signaling circuitry of CLL cells, we quantified the effect of the SDF-1, BAFF, APRIL, anti-IgM, interleukin-4 (IL4) and secreted CD40L (sCD40L) on the survival of in vitro cultured CLL cells and found IL4 and sCD40L to be most efficient in rescuing CLL cells from apoptosis. In quantitative dose-response experiments using cell survival as readout, the binding affinity of IL4 to its receptor was similar between malignant and non-malignant cells. However, the downstream signaling in terms of the amount of STAT6 and its degree of phosphorylation was highly stimulated in CLL cells. In contrast, the response to sCD40L showed a loss of cooperative binding in CLL cells but displayed a largely increased ligand binding affinity. Although a high-throughput microscopy analysis did not reveal a significant difference in the spatial CD40 receptor organization, the downstream signaling showed an enhanced activation of the NF-kB pathway in the malignant cells. Thus, we propose that the anti-apoptotic phenotype of CLL involves a sensitized response for IL4 dependent STAT6 phosphorylation, and an activation of NF-kB signaling due to an increased affinity of sCD40L to its receptor.CLL (chronic lymphocytic leukemia), the most common leukemia in the western world, is characterized by the accumulation of mature CD5 1 B cells in the blood, bone marrow and secondary lymphoid organs in patients due to extended survival and resistance to apoptosis. Enhanced CLL cell survival is triggered by microenvironmental signals as evident by the fact that CLL cells rapidly undergo apoptosis when cultured without support in vitro.1,2 This dependency can be mimicked in vitro by the addition of cytokines to the medium or by co-culturing with bone marrow derived stromal cell lines that lead to an increased survival time of CLL cells. However, it is currently an open question whether an enriched microenvironment is the sole cause for prolonged CLL cell survival. Alternatively, CLL cells could have a higher sensitivity to respond to survival stimuli as compared to nonmalignant B cells due to deregulated intracellular signaling. Intriguingly, interactions between malignant lymphocytes and non-transformed cells are bidirectional and lead to the establishment of an abnormal microenvironment that is able to inhibit apoptosis of neoplastic B cells. 3,4 The interaction of CLL cells with non-malignant bystander cells like T lymphocytes and stromal cells supports CLL survival either directly (through cell-cell interaction) or indirectly (by secreting soluble factors into the serum). 5,6 Stromal cells, such as nurselik...

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Chronic Lymphocytic Leukemia B Cells Can Express CD40 Ligand and Demonstrate T-Cell Type Costimulatory Capacity

Cited by 73 publications

References 51 publications

CD8+ chronic lymphocytic leukemia: an extensive characterization of a bizarre hybrid neoplasia

CD8+ chronic lymphocytic leukemia: an extensive characterization of a bizarre hybrid neoplasia

A phase 1 study of lucatumumab, a fully human anti‐CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma

Loss of cooperativity of secreted CD40L and increased dose-response to IL4 on CLL cell viability correlates with enhanced activation of NF-kB and STAT6

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