Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number

Podhorecka, Monika; Gorący, Aneta; Szymczyk, Agnieszka; Kowal, Małgorzata; Ibáñez, Blanca Gil; Jankowska-Łęcka, Olga; Macheta, Arkadiusz; Nowaczyńska, Aleksandra; Drab-Urbanek, Elzbieta; Chocholska, Sylwia; Jawniak, Dariusz; Hus, Marek

doi:10.18632/oncotarget.16148

Cited by 29 publications

(31 citation statements)

References 32 publications

(44 reference statements)

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“…In plasma obtained from ibrutinib-treated patients, Th2 and Th1 cytokines decreased, while the Th1:Th2 ratio remained stable, after 12 months of treatment [17]. Although a decrease in Th2-type cytokines has been reported by several groups, a change in Th1-type cytokines has been less consistent [10,16,17,19,37].…”

Section: Th1 and Th2 Polarizationmentioning

confidence: 95%

“…FOXP3 + Tregs expand in response to low doses of ibrutinib, but are inhibited at higher doses [46]. In patients receiving ibrutinib, a decrease of FOXP3 + Tregs was observed during the first two months of therapy [19,37]. Further, decreases in Th17 cells (CXCR3 − CCR6 + ) and Th17-mediated cytokines such as IL-17A, IL-21 and IL-23 were observed in the serum or plasma of CLL patients treated with ibrutinib [16,17].…”

Section: Th17 and Tregs Balancementioning

confidence: 99%

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Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

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Section: Th1 and Th2 Polarizationmentioning

confidence: 95%

Section: Th17 and Tregs Balancementioning

confidence: 99%

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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“…Preclinical data also suggest that ibrutinib may help repair the T cell defects in CLL 41 . Multiple studies have reported that ibrutinib decreases Th2 cytokines in vivo [41][42][43] , normalizes total T cell numbers 42 and decreases T regulatory cells 43 , during the first six months of therapy. Despite these observations, as ibrutinib is widely used, it is clear that susceptibility to infection remains significant.…”

Section: Infections and Prophylaxis (Including Vaccines)mentioning

confidence: 99%

How I treat CLL patients with ibrutinib

Brown

2018

Blood

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Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.

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“…In patients treated with ibrutinib, the increased T cell numbers normalized and production of inflammatory cytokines were reduced, and the T cell repertoire diversity increased [177,178]. Ibrutinib also reduced Treg numbers [179]. Expression of PD-1 and PD-L1 upon ibrutinib treatment markedly decreased, improving activated effector T cell functions [180,181].…”

Section: Therapeutic Options In Cllmentioning

confidence: 99%

SLAMF6 in health and disease: Implications for therapeutic targeting

Yigit

Wang

Herzog

et al. 2019

Clinical Immunology

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Effective immune responses develop after a well-orchestrated series of events that include recognition, immune cell interactions and activation/inhibition of signaling pathways. The signaling lymphocyte activation molecule family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins (SLAMF1-9) expressed at different levels, are involved in viral and bacterial recognition, serve as co-stimulatory molecules at immune synapses, and modulate myeloid and lymphocyte development. SLAMF receptors are homophilic receptors, with the exception of SLAMF2 and SLAMF4, and are only expressed on hematopoietic cells. Their adaptors, SLAM associated protein (SAP) and Ewing's sarcoma-associated transcript 2 (EAT-2), bind to the cytoplasmic tails and control the functions and magnitude of SLAMF receptor signaling. In this review, we focus on the current knowledge on the role of SLAMF6 receptor in regulating immune functions and recent findings describing how SLAMF6 can be exploited as a target in human malignancies. The SLAM family of immune cell surface receptors is a member of the CD2 subfamily of the immunoglobulin (Ig) superfamily consisting of nine members, SLAMF1-9 [1-4]. SLAMF receptors are type I transmembrane glycoproteins comprised of an extracellular membrane containing an N-terminal V-Ig domain followed by a C2-Ig domain in the extracellular region (this set is duplicated in SLAMF3), a transmembrane region, and an intracellular cytoplasmic tail containing tyrosine based switch motifs (ITSM). Notable exceptions to this structure include SLAMF2, which has a glycosyl-phosphatidyl-inositol (GPI) membrane anchor and like SLAMF8 and SLAMF9 lack ITSM motifs [5-8]. Binding of SLAM associated adaptors; SAP and EAT-2, to cytoplasmic tails of various SLAMFs regulate their function on different immune cells. Expression of SLAMFs and their adaptors is restricted to hematopoietic cells. In addition, the gene loci are located on chromosome 1 in both mice and humans, except SAP, which is located on the X chromosome [9](Figure 1). All SLAMFs are homophilic receptors aside from SLAMF2 and SLAMF4, which bind each other [10-12]. The determination of the SLAMF3, SLAMF5 and SLAMF6 crystal structures revealed in-trans interactions through their IgV domains (SLAMF3 unpublished data, generously donated by Profs. Steve Almo and Stanley Nathenson, Albert Einstein College of Medicine (Figure 2) [13, 14]. Engagement of SLAMF ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T receptors on immune cells (e.g. APC -T cell) trigger inhibitory or activating signals that modulate cellular responses. Within these homophilic and heterophilic interactions, the binding affinities for each SLAMF varies (SLAMF3 nM, SLAMF5 sub-M, SLAMF6 ~ 2M, SLAMF2/4 ~4M, SLAMF1 ~200 M) which likely contributes to functional differences within the family of receptors [12-15]. In addition to being self-ligands, SLAMF1 also serves as an entry receptor for Measles virus [16, 17] while SLAMF1, SLAMF2 and SLAMF6 have been demonstrated to interact...

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Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number

Cited by 29 publications

References 32 publications

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

How I treat CLL patients with ibrutinib

SLAMF6 in health and disease: Implications for therapeutic targeting

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