Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function

DiLillo, David J.; Weinberg, J. Brice; Yoshizaki, Ayumi; Horikawa, Mayuka; Bryant, Jacquelyn M.; Iwata, Y.; Matsushita, T.; Matta, Karen; Chen, Y; Venturi, Guglielmo M.; Russo, Giandomenico; Gockerman, Jon P.; Moore, Joseph O.; Diehl, Louis F.; Volkheimer, Alicia D.; Friedman, Daphne R.; Lanasa, Mark C.; Hall, Russell P.; Tedder, Thomas F.

doi:10.1038/leu.2012.165

Cited by 156 publications

(160 citation statements)

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“…41,43 In keeping with these observations, CLL cells cultured under hypoxia sharply upregulated IL10 mRNA ( Figure 3D), the hallmark cytokine of regulatory B cells. 44 This upregulation appeared partly mediated through A2A signaling, as receptor blockade with SCH58261 prevented IL-10 increase. Consistently, a high number of IL-10 1 CLL cells were detected in CLL LN, in contrast to reactive LN sections ( Figure 3E-G).…”

Section: Resultsmentioning

confidence: 99%

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

et al. 2016

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Key Points• Hypoxia shapes the CLL lymph node microenvironment by acting through the A2A adenosine receptor.• Inhibiting the A2A adenosine receptor counteracts the effects of hypoxia on CLL cells, macrophages, and T lymphocytes. adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients.

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Section: Resultsmentioning

confidence: 99%

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

et al. 2016

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“…Recent studies suggest that CLL cells have the functional capacity to express and secrete interleukin (IL)-10, 60 a property that characterizes a subset of B cells with immune regulatory functions (B-10 cells). 61 Based on the observation in Em-TCL1 mice that the expansion of IL-10-competent malignant B cells precedes the development of overt leukemia, IL-10 production was suggested to participate in the immunoregulatory capacity of the malignant cells and therefore influence disease progression, outcome, and response to treatment, 60 possibly through suppression of the antitumor response.…”

Section: Phenotypic and Epigenetic Characteristicsmentioning

confidence: 99%

“…61 Based on the observation in Em-TCL1 mice that the expansion of IL-10-competent malignant B cells precedes the development of overt leukemia, IL-10 production was suggested to participate in the immunoregulatory capacity of the malignant cells and therefore influence disease progression, outcome, and response to treatment, 60 possibly through suppression of the antitumor response. As observed in CLL patients, leukemic Em-TCL1 mice display multiple T-cell alterations, including the shift from a naïve to a memory T-cell subtype 62 and defective signal transduction at the immune synapse.…”

Section: Phenotypic and Epigenetic Characteristicsmentioning

confidence: 99%

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Simonetti

Bertilaccio

Ghia

et al. 2014

Blood

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Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for preclinical studies. Several genetically engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? Here we compare the various CLL mouse models with regard to disease phenotype, penetrance, and severity. We discuss similarities and differences of the murine lymphoproliferations compared with human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire, and disease course show close resemblance to the human disease. We conclude that modeling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.

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“…Although the expression of many genes was altered, one of the most significantly altered transcripts was Lgals1 (Gal-1), whereas other known immunosuppressive tumor-associated molecules, 13 including the inhibitory cytokine IL-10, 11,14,33 were unaltered. Although all lymphomas expressed Lgals1, Lgals1 expression levels correlated significantly with lymphoma sensitivity to CD20 immunotherapy (r 5 20.70, P # .001; Figure 6A).…”

Section: Lymphoma Families As a Preclinical Model Of Lymphoma Developmentioning

confidence: 99%

Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms

Lykken

Horikawa

Minard‐Colin

et al. 2016

Blood

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Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function

Cited by 156 publications

References 50 publications

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms

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