Ibrutinib induces rapid down‐regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia‐related genes in blood and lymph nodes

Palma, Marzia; Krstić, Aleksandra; Peña-Pérez, Lucía; Berglöf, Anna; Meinke, Stephan; Wang, Qing; Blomberg, K. Emelie M.; Kamali‐Moghaddam, Masood; Shen, Qiujin; Jaremko, Georg; Lundin, Jeanette; Paepe, Annick De; Höglund, Petter; Kimby, Eva; Österborg, Anders; Månsson, Robert; Smith, C. I. Edvard

doi:10.1111/bjh.15516

Cited by 17 publications

(35 citation statements)

References 41 publications

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“…In addition, the authors showed that CD84 silencing not only downregulates PD-L1 expression on CLL cells and in the microenvironment, but it also affects PD-1 expression on the T cell compartment, suggesting a central role of CD84 in driving immunomodulatory signaling [63]. Lastly, treatment with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib was also found to decrease PD-1/PD-L1 expression, thereby affecting T cell proliferation and pseudoexhaustion, with important implication in the disease outcome [64][65][66][67][68][69].…”

Section: Programmed Cell Death 1 (Pd-1)/programmed Cell Death Ligand mentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

103

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Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.

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Section: Programmed Cell Death 1 (Pd-1)/programmed Cell Death Ligand mentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

103

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“…20,22 Ibrutinib reduces BCR signaling by inhibiting BTK and is a promising alternative for treating MCL, CLL and other B-cell malignancies. 30,58 However, some MCL and CLL patients are refractory to Ibrutinib treatment. 12,59 Here, we showed that JeKo-1 but not REC-1 MCL cells require BCR signaling for their migration and adhesion to stromal cells, suggesting that Although there is no obvious explanation for the apparent clustering of the MCL patient samples into two separate groups, it is interesting to note that clustering of differentially expressed microenvironment/ adhesion related genes led to separation of MCL patient samples into two groups.…”

Section: Discussionmentioning

confidence: 99%

“…28 In CLL, Ibrutinib causes redistribution of tumor cells from lymph nodes (LN) into the peripheral blood (PB) and inhibits their migration towards CXCL12 gradients. 26,29,30 Furthermore, Ibrutinib treatment of MCL reduced the secretion of the BCR-associated chemokines CCL3 and CCL4 and decreased the number of adherent cells in co-culture. 31 For patients with relapsed or refractory MCL or CLL after conventional treatment, Ibrutinib is considered the drug of choice.…”

Section: Introductionmentioning

confidence: 97%

Differential B-cell receptor signaling requirement for adhesion of mantle cell lymphoma cells to stromal cells

Sadeghi

Arvidsson

Merrien

et al. 2020

Preprint

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AbstractInteractions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, which exhibited different patterns of stromal cell adhesion and chemotactic migration towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. 590 genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR signaling by siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1 but not REC-1 cells to stromal cells. Cell surface levels of CXCR4 were higher in JeKo-1 cells and CXCR4 was important for migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 plays a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. The results presented here provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.

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“…The BTK inhibitors (ibrutinib, acalabrutinib), IKKβ inhibitors (aspirin) and JAKs inhibitors (tofacitinib, ruxolitinib, baricitinib, lestaurtinib and pacritinib) are used to treat autoimmune and myelodysplastic diseases . Ibrutinib, introduced to treat chronic lymphocytic leukaemia, reduced plasma levels of 10 inflammation markers, mostly chemokines …”

Section: Intracellular Therapies That Target Signal Transducers In Prmentioning

confidence: 99%

“…201 Ibrutinib, introduced to treat chronic lymphocytic leukaemia, reduced plasma levels of 10 inflammation markers, mostly chemokines. 202 As the JAK family comprises four members (JAK1, 2, 3 and TYK2), some inhibitors are mono-selective while others target two or more members of the family. JAK inhibitors are effective in myeloproliferative diseases, rheumatoid arthritis, psoriasis and ulcerative colitis but not in Crohn's disease.…”

Section: Inhibitors Of Kinases In Proinflammatory Transcriptional Cmentioning

confidence: 99%

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Hawiger

Zienkiewicz

2019

Scand J Immunol

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Inflammation is the mechanism of diseases caused by microbial, autoimmune, allergic, metabolic and physical insults that produce distinct types of inflammatory responses. This aetiologic view of inflammation informs its classification based on a cause‐dependent mechanism as well as a cause‐directed therapy and prevention. The genomic era ushered in a new understanding of inflammation by highlighting the cell's nucleus as the centre of the inflammatory response. Exogenous or endogenous inflammatory insults evoke genomic responses in immune and non‐immune cells. These genomic responses depend on transcription factors, which switch on and off a myriad of inflammatory genes through their regulatory networks. We discuss the transcriptional paradigm of inflammation based on denying transcription factors’ access to the nucleus. We present two approaches that control proinflammatory signalling to the nucleus. The first approach constitutes a novel intracellular protein therapy with bioengineered physiologic suppressors of cytokine signalling. The second approach entails control of proinflammatory transcriptional cascades by targeting nuclear transport with a cell‐penetrating peptide that inhibits the expression of 23 out of the 26 mediators of inflammation along with the nine genes required for metabolic responses. We compare these emerging anti‐inflammatory countermeasures to current therapies. The transcriptional paradigm of inflammation offers nucleocentric strategies for microbial, autoimmune, metabolic, physical and other types of inflammation afflicting millions of people worldwide.

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Ibrutinib induces rapid down‐regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia‐related genes in blood and lymph nodes

Cited by 17 publications

References 41 publications

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Differential B-cell receptor signaling requirement for adhesion of mantle cell lymphoma cells to stromal cells

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

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