Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia

Damien Saulep, Fabien Vincent, Melanie Le Page, Andrew Wei, Stephen Bek Ngie Ting, Carlo M Croce, Constantine Tam, Fabienne Mackay-Fisson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNa) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNa production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-? and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.
Original languageEnglish
Pages (from-to)2005 - 2015
Number of pages11
JournalLeukemia
Volume28
Issue number10
DOIs
Publication statusPublished - 2014

Cite this

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title = "Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia",
abstract = "Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNa) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNa production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-? and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.",
author = "Damien Saulep and Fabien Vincent and {Le Page}, Melanie and Andrew Wei and Ting, {Stephen Bek Ngie} and Croce, {Carlo M} and Constantine Tam and Fabienne Mackay-Fisson",
year = "2014",
doi = "10.1038/leu.2014.105",
language = "English",
volume = "28",
pages = "2005 -- 2015",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Macmillan Publishers",
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Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia. / Saulep, Damien; Vincent, Fabien; Le Page, Melanie; Wei, Andrew; Ting, Stephen Bek Ngie; Croce, Carlo M; Tam, Constantine; Mackay-Fisson, Fabienne.

In: Leukemia, Vol. 28, No. 10, 2014, p. 2005 - 2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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AU - Saulep, Damien

AU - Vincent, Fabien

AU - Le Page, Melanie

AU - Wei, Andrew

AU - Ting, Stephen Bek Ngie

AU - Croce, Carlo M

AU - Tam, Constantine

AU - Mackay-Fisson, Fabienne

PY - 2014

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N2 - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNa) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNa production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-? and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.

AB - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNa) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNa production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-? and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.

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