Dr. Nicholas Chiorazzi
Feinstein Institute for Medical Research
Dr. Maria Theresa Sabrina-Bertilaccio
University of Texas MD Anderson Cancer Center
In this project we will exploit in vivo and in vitro systems of CLL to: a) investigate, at molecular level to what extent CLL malignant lymphocytes depend on the support of TAMs; b) elucidate how the manipulation of leukemic cell/TAM interactions impacts on other immune cells of the microenvironment; c) finalize the in vitro and mouse systems results to design novel therapeutic strategies to be translated into clinical practice.
Dr. Jan Burger
University of Texas MD Anderson Cancer Center
Zeev Estrov, M.D.
University of Texas MD Anderson Cancer Center
The intent behind this study is to: a) Determine how CLL-derived exosomes “educate” monocytes; b) Isolate, expand and study the characteristics of CLL patients’ fibrocytes; c) Investigate the effects of CLL-derived fibrocytes on hematopoietic cells; d) Determine whether fibrocytes play a role in CLL bone marrow failure and whether serum amyloid P (SAP) could reverse it.
Much attention has been paid to the role of T-lymphocytes in the CLL microenvironment whereas little is known about the role of monocytes or monocyte-derive cells. A few studies suggested that monocytes and monocyte-derived cells play a role in the pathogenesis of CLL: a) A high monocyte count was found to correlate with CLL patients’ poor prognosis; b) Increased frequency of CD14+ /HLA-DRlo/neg monocytes was associated with decreased time to progression; c) Monocytes were shown to increase the survival of CLL cells by secreting soluble CD14, which induces nuclear factor-κB (NF-κB) activation in CLL cells; d) Monocyte-derived nurse-like cells were shown to provide CLL cells with survival advantage; and e) A recent study demonstrated that the survival of CLL cells, in a mouse model, is macrophage-dependent. This data suggests that a cross-talk between CLL cells and monocytes exists and that monocyte-derived cells support, protect and/or stimulate the CLL clone.
Dr. Katy Rezvani
University of Texas MD Anderson Cancer Center
Chronic lymphocytic leukemia (CLL) is characterized by generalized immune suppression and susceptibility to infectious complications and secondary malignancies. A number of studies have reported both quantitative and qualitative defects in T-cell function in CLL. However, the mechanisms underlying CLL-induced immunosuppression have been difficult to dissect, as they involve complex bidirectional interactions among leukemic cells, components of the tumor microenvironment and immune effectors. Regulatory B cells (Bregs) are a recently defined subset of B cells with potent immunoregulatory function. A subset of Bregs, known as B10 cells, suppress effector T-cell function through STAT3-mediated production of IL-10 and have been implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, immune thrombocytopenia, active chronic sarcoidosis, and multiple sclerosis, as well as alloimmune disorders such as graft-versus-host disease. Tedder et al recently reported that CLL B cells are capable of secreting IL-10 and possess regulatory functions comparable to those of normal B10 cells. These intriguing observations suggest a means by which CLL cells could induce immunosuppression in patients, but a mechanistic basis for IL-10 production by CLL cells is lacking.
The CLL microenvironment supports tumor cell survival via a number of soluble and surface–bound factors, such as the CXC chemokine ligand 12 (CXCL12), BAFF, APRIL and CD40 ligand (CD154). CXCL12 binds its receptor CXCR4 on the surface of CLL cells and directs chemotaxis, supports tumor survival and activates various signaling pathways, including STAT3. We hypothesize that CXCL12-CXCR4 interaction results in activation of the STAT3 pathway and IL-10 production by CLL cells, which may in turn contribute to immune suppression in patients. We will test this hypothesis in the following specific aims:
Aim 1. Determine if the CXCL12-CXCR4 chemokine ligand/receptor axis activates the STAT3 pathway and CLL B10 function
Aim 2. Determine if CLL induces T cell suppression through phosphorylation of Y705-STAT3
Aim 3. Investigate if lenalidomide modulates T cell function in CLL by inhibiting the STAT3 pathway