Abstract LB-230: SOCS5 mediates defective function of monocyte-derived dendritic cells in patients with chronic lymphocytic leukemia
Authors: Patricia A. Toniolo, Suhu Liu, Sarah R. Walker, Jose Alexandre M. Barbuto, David A. Frank
Journal: Cancer Research (2015)

Abstract Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries. This clinically heterogeneous disease is characterized by the progressive accumulation of monoclonal B cells co-expressing CD5, CD19, CD20 and CD23 in the peripheral blood and in the primary and secondary lymphoid organs. Additionally, a range of immune cells are altered in patients with CLL. The resulting immunologic defects predispose patients to severe recurrent infections, which is the major life-threatening complication associated with CLL. Functional impairment of dendritic cells (DCs) in CLL not only diminishes the response to microorganisms, but it also allows for tumor escape from immune control. Understanding the mechanism for this effect can provide insight into the molecular regulation of DC function and may also suggest therapeutic strategies to reverse the immunosuppressive effect of tumors on DCs. To elucidate the mechanism for DC dysfunction in patients with CLL, we focused on signal transduction pathways that regulate the expression of genes necessary for the immune response. We found that monocytes from CLL patients have a decrease in IL-4-induced activation of the transcription factor STAT6, which prevents the phenotypic and functional maturation of DCs. This does not reflect a generalized defect in cytokine-induced signal transduction, as the activation of the related transcription factor STAT5 in response to GM-CSF is unaffected. Monocyte-derived DCs from CLL patients display low levels of HLA-DR, costimulatory molecules and CD83, and reduced secretion of pro-inflammatory cytokines. These changes are associated with low expression of TLR4 and related molecules, which decrease the ability of these cells to respond to stimulus afforded by LPS, impairing their complete maturation. Consequently, monocyte-derived DCs from CLL patients have decreased ability to induce proliferation of T-cells and display an increased induction of immune-suppressive regulatory T cell. Although monocytes from CLL patients exhibit high IL-4R expression, activation of the downstream transcription factor STAT6 is inhibited because of increased expression of the negative regulator SOCS5. It is known that CLL cells produce IL-10, leading to elevated serum levels of this cytokine. IL-10-treatment of monocytes from healthy donors mimics the alteration in signaling observed in patients, through enhanced STAT3-dependent expression of SOCS5, which inhibits STAT6 activation and leads to defective DC differentiation. These findings suggest that SOCS5 can mediate the impaired function of DCs in CLL patients, and may be a new potential therapeutic target for reversing cancer-associated immune suppression. Note: This abstract was not presented at the meeting. Citation Format: Patricia A. Toniolo, Suhu Liu, Sarah R. Walker, Jose Alexandre M. Barbuto, David A. Frank. SOCS5 mediates defective function of monocyte-derived dendritic cells in patients with chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-230. doi:10.1158/1538-7445.AM2015-LB-230