Restoring immunocompetency in Chronic Lymphocytic Leukemia
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Chronic Lymphocytic Leukaemia (CLL) is a clinically heterogeneous disease caused by the clonal expansion of mature B lymphocytes that accumulate in the blood, bone marrow, lymph nodes and spleen. Some patients remain stable for many years without therapy (indolent) but eventually succumb to unrelated diseases, whereas others develop an aggressive and symptomatic form of CLL despite therapy (progressive).
Patients with CLL also show severe systemic immunodeficiency, mainly manifested as hypogammaglobulinaemia. Even with intravenous immunoglobulin therapy and modern antibiotics, over a quarter of CLL patients will still die of an infection despite effective treatment of tumour burden. Processes leading to the severe immune defects in CLL patients are not fully understood but involve multi-directional interactions and aberrant cytokine production between CLL cells, immune cells and their microenvironment that favour CLL cell persistence and ultimately, progression at the expense of normal immune cell function. Moreover, current CLL treatments exacerbate the immunodeficiency observed in these patients.
Recent studies have shown that CLL cells produce IL-10, an immunosuppressive cytokine that may shut down anti-tumour immunity and hence indirectly promote CLL cell survival. As such, CLL cells act as regulatory cells similar to regulatory IL-10-producing B cells (B10 cells), suggesting a possible contribution of CLL cells to immunosuppression. New exciting data from Prof. Mackay’s lab show that CLL cells produce IL-10 in response to the cytokine BAFF. BAFF is a TNF-like cytokine critical for B cell maturation and survival, and is implicated in the development and progression of CLL. Indeed, elevated BAFF levels have been measured in sera from CLL patients, suggesting that BAFF plays a role in the persistence of CLL cells. All 3 BAFF receptors, BAFF-R, TACI and BCMA, are expressed on CLL cells. Preliminary data from the group show that BAFF driven IL-10 production by CLL cells is mediated via the receptor TACI, as TACI inhibition (using an anti-TACI blocking mAb) resulted in attenuated IL-10 secretion. However, TACI is also a negative regulator of B cells and its exact role in the progression of CLL requires to be dissected.
The aim of this project is to dissect the contribution of TACI both as a regulator of B cells but also as a receptor critical for IL-10 production , in the development and progression of CLL. For this we will use an animal model of CLL called TCL1 Tg mice. This model will be combined with a mouse model lacking TACI in all cells or specifically lacking TACI in some tissues. The project involves monitoring the animals for CLL development but also testing test the ability of their immune system to respond to immunisation. We also use models of CLL cell transfer into various genetically-modified recipient mice to test the progression of CLL in a a modified environment. These experiments will uncover molecules and pathways that are required for CLL progression and help us identify therapeutic targets that are potentially amenable for therapy development. We also have a collaboration with haematologists who can supply patient samples to validate some of these discoveries.
Dr Andrew Wei, Monash University, Clayton
Dr Constantine Tam, Peter MacCallum Institute, Melbourne
Professor David Huang, Walter Eliza Hall Institute, Parkville
Professor Carlo Croce, Ohio State University College of Medicine
2014-2017 NHMRC project grant: Restoration of immune competency in CLL $557,565
2014-2017 Worldwide Cancer Research (UK) CLL £192,070
2016-2018 Victorian Cancer Agency Early Career Seed Grants $200,000
- Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol 2009;9: 491-502.
- Saulep-Easton D, Vincent FB, Le Page M, Wei A, Ting SB, Croce CM, Tam C, Mackay F. Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia. Leukemia 2014 Oct;28(10): 2005-15. doi: 10.1038/leu.2014.105. Epub 2014 Mar 18.
- Saulep-Easton D, Vincent FB, Quah PS, Wei A, Ting SB, Croce CM, Tam C, Mackay F. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia. 2016 Jan;30(1):163-72. doi: 10.1038/leu.2015.174. Epub 2015 Jul 3.
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