Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells

Idler, Irina; Giannopoulos, Krzysztof; Zenz, Thorsten; Bhattacharya, Nupur; Nothing, Maria; Döhner, Hartmut; Stilgenbauer, Stephan; Mertens, Daniel

doi:10.1111/j.1365-2141.2009.08014.x

Cited by 53 publications

(43 citation statements)

References 10 publications

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“…Furthermore, because Th17 cells secrete a variety of cytokines (e.g., IL-17A, IL-17F, CCL20, IL-21, and IL-22), the beneficial effects in CLL could be due to the actions of any one or a combination of these. Previous reports indicated that three patients with CLL who responded to lenalidomide had higher levels of Th17 cells and lower levels of Treg 34 and that IL-21, which can be secreted by Th17 cells, promotes apoptosis of CLL cells. 37 Our preliminary analysis (not shown) on IL-17 receptor family members (RA, RB, RC and RD) suggest that IL-17 receptors are expressed at varying levels on CLL and normal B cells, T cells, and monocytes, in increasing order.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, elevated levels of Th17 cells have been found in patients with a favorable response to therapy in breast and prostate cancer and melanoma, 36 and acute myeloid leukemia. 28 Eleven of our 66 patients analyzed had received treatment (Online Supplementary Table S1), raising the possibility that therapy could influence these numbers, and indeed certain treatments, such as lenalidomide, can lead to higher Th17 levels, 34 whereas others, such as rituximab, can lower Th17 cell numbers. 35 However, because treated patients were equally distributed between the Th17…”

Section: Discussionmentioning

confidence: 99%

“…Since certain treatments can alter Th17 cell numbers, 34,35 we compared overall survival in patients whose samples were taken prior to any therapy (n=55) ( Figure 4B). Overall, patients whose PBMC were collected before therapy and who fell into the Th17…”

Section: The Absolute Numbers Of Circulating Th17 Cells In Chronic Lymentioning

confidence: 99%

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Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance

Jain¹,

Javdan²,

Feger³

et al. 2011

Haematologica

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance

Jain¹,

Javdan²,

Feger³

et al. 2011

Haematologica

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“…22 Increased Th17 with lenalidomide may have a protective role against CLL progression. 23 In contrast, induction of Th17 cells and associated cytokines may increase the possibility of complications such as autoimmune cytopenias. Accordingly, increased Th17 cells have been detected in patients experiencing autoimmune cytopenias, with a decreased Treg-to-Th17 ratio.…”

mentioning

confidence: 99%

“…24 Although still unconfirmed, it is suspected that IL-10 secretion by malignant B cells may modulate Treg/Th17 differentiation. 22,23,25 Terminally differentiated and exhausted T cells Patients with CLL have been shown to have decreased naive T cells and a shift toward the CD8 1 effector memory phenotype. [26][27][28] The accumulation of terminal memory in CLL may be a result of chronic antigen stimulation.…”

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confidence: 99%

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

2017

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Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies. Here, we review T-cell abnormalities in preclinical models and patient samples, finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders.

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The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients

et al. 2013

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Angiogenesis has been shown to substantially contribute to the progression of chronic lymphocytic leukemia (CLL). Neuropilin-1 (NRP1) represents a receptor for vascular endothelial growth factor (VEGF), which has been reported to be overexpressed in several malignancies. In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed. Earlier we described the specific Treg reduction during the therapy with thalidomide in vivo. Now we observe the reduction of the NRP1 expression on Tregs in vitro, thereby suggesting a possible target of thalidomide action. In conclusion, NRP1 might represent an interesting link between angiogenesis and tolerance mechanisms and represents interesting target for therapy.

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Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells

Cited by 53 publications

References 10 publications

Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance

Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients

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