Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients

Boissard, Frédéric; Jj, Fournié; Quillet‐Mary, Anne; Ysebaert, Loïc; Poupot, Mary

doi:10.1038/bcj.2015.74

Cited by 46 publications

(49 citation statements)

References 12 publications

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“…We could imagine that high blood level of sLFA-3 favors a defective CLL cells/T cells synapse as CD2 is involved as an accessory molecule in the T cell receptor signaling [ 39 ]. However, as NLC are only located in TME [ 49 ], nursing effect of NLC for CLL cells in TME would not be impaired by sLFA-3, favouring the disease progression. We also propose that idelalisib therapy, even in the frontline setting, may specifically alleviate this detrimental effect of NLC/CLL in the TME through decreased LFA-3 expression in CLL cells, an effect that was not observed with ibrutinib in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…We also propose that idelalisib therapy, even in the frontline setting, may specifically alleviate this detrimental effect of NLC/CLL in the TME through decreased LFA-3 expression in CLL cells, an effect that was not observed with ibrutinib in vitro . Accordingly, we recently published data suggesting that idelalisib alone is more effective than ibrutinib (at the same clinically-relevant dose of 0.5 μM) in combating the pro-survival effects of NLC [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

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Nurse-like cells promote CLL survival through LFA-3/CD2 interactions

et al. 2016

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In the tumoral micro-environment (TME) of chronic lymphocytic leukemia (CLL), nurse-like cells (NLC) are tumor-associated macrophages which play a critical role in the survival and chemoresistance of tumoral cells. This pro-survival activity is known to involve soluble factors, but few data are available on the relative role of cells cross-talk. Here, we used a transcriptome-based approach to systematically investigate the expression of various receptor/ligand pairs at the surface of NLC/CLL cells. Their relative contribution to CLL survival was assessed both by fluorescent microscopy to identify cellular interactions and by the use of functional tests to measure the impact of uncoupling these pairs with blocking monoclonal antibodies. We found for the first time that lymphocyte function-associated antigen 3 (LFA-3), expressed in CLL at significantly higher levels than in healthy donor B-cells, and CD2 expressed on NLC, were both key for the specific pro-survival signals delivered by NLC. Moreover, we found that NLC/CLL interactions induced the shedding of soluble LFA-3. Importantly, in an exploratory cohort of 60 CLL patients receiving frontline immunochemotherapy, increased levels of soluble LFA-3 were found to correlate with shorter overall survival. Altogether, these data suggest that LFA-3/CD2 interactions promote the survival of CLL cells in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nurse-like cells promote CLL survival through LFA-3/CD2 interactions

et al. 2016

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“…Although ibrutinib has shown excellent effects on CLL cell component inducing mobilization of lymphocytes from tissue into the blood with the consequent cell death, recently different studies have demonstrated the on-target effects on off-tumor cells related to tumor microenvironment. In particular, ibrutinib targets BTK expressed by NLC exacerbating the immunosuppressive profile and probably supporting the protection of residual CLL cells inside tissue niches ( 11 , 18 , 19 ). Acalabrutinib is a potent highly selective BTK inhibitor, FDA-approved for the treatment of CLL, with different rate of infections in preliminary reports ( 20 – 22 ).…”

Section: Introductionmentioning

confidence: 99%

BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia

et al. 2020

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Infections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by Aspergillus fumigatus determining an exacerbation of an immunosuppressive signature, a reduction of phagocytosis and a significant deficit in the secretion of inflammatory cytokines either in macrophages and monocytes isolated from CLL patients and healthy donors. These effects lead to a failure in completely counteracting conidia germination. In addition we investigated the biological effects of ibrutinib on monocyte counterpart in patients who were undergoing therapy. A significant impairment in cytokine secretion and a deficit of phagocytosis in circulating monocytes were detected after 3 months of treatment. Thus, our results uncover modifications in the innate response in CLL patients induced by ibrutinib that may impair the immunological response to fungal infection. KEYPOINTS BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during Aspergillus fumigatus infection. Reduction of TNF-α secretion and phagocytosis are detected in monocytes isolated from CLL patients during ibrutinib therapy.

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“…In addition, examination of bone marrow trephines from ibrutinib treated patients revealed reduced interaction between CLL cells and TAMs [73]. Finally, Boissard noted that NLCs protected CLL cells from the apoptotic effects of therapeutic concentrations of ibrutinib in vitro [74]. Combined, these data suggest that the direct anticancer activity of ibrutinib on CLL cells may be aided by i) a reduced ability to recruit TAMs to the CLL niche and ii) an inhibition of direct CLL:TAM interaction.…”

Section: Tams/nlcs As a Therapeutic Targetmentioning

confidence: 97%

“…Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib, have shown great promise in CLL with durable responses in both relapsed/refractory [71] disease and as an initial treatment [72]. Whilst these effects are generally attributed to the action of BTK inhibition on BCR function and B cell survival there is emerging evidence that part of their success is attributable to effects on macrophages and other immune effector cells [73,74]. For example, evaluation of blood samples and bone marrow trephines from a phase II study of 80 patients receiving ibrutinib showed marked reductions in multiple cytokines such as CCL3, CCL4 & CXCL13 [73].…”

Section: Tams/nlcs As a Therapeutic Targetmentioning

confidence: 99%

The duality of macrophage function in chronic lymphocytic leukaemia

Chen

Mapp

Blumenthal

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and, in some patients, is accompanied by resistance to both chemotherapeutics and immunotherapeutics. In this review we will discuss the role of tumour associated macrophages (TAMs) in promoting CLL cell survival and resistance to immunotherapeutics. In addition, we will discuss mechanisms by which TAMs suppress T-cell mediated antitumour responses. Thus, targeting macrophages could be used to i) reduce the leukaemic burden via the induction of T-cell-mediated antitumour responses, ii) to reduce pro-survival signalling and enhance response to conventional chemotherapeutics or iii) enhance the response to therapeutic antibodies in current clinical use.

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Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients

Cited by 46 publications

References 12 publications

Nurse-like cells promote CLL survival through LFA-3/CD2 interactions

Nurse-like cells promote CLL survival through LFA-3/CD2 interactions

BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia

The duality of macrophage function in chronic lymphocytic leukaemia

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