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

Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia (#S-15)

D Easton 1 , F Vincent 1 , M Le Page 1 , A Wei 2 , SB Ting 3 , CM Croce 4 , C Tam 2 , Fabienne Mackay 1
  1. Monash University, Central Clinic School, Melbourne, VIC, Australia
  2. Department of Haematology, Peter MacCallum Cancer Centre, Melbourne
  3. Department of Haematology, The Alfred Hospital, Melbourne
  4. Department of Molecular Virology, The Ohio State University, Columbus, Ohio, USA

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 function underpins 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-b 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.