Survival and growth of cancer cells depend on environmental cues delivered by cell contact and soluble factors. These shape disease biology and aggressiveness, reflected by the effectiveness of therapeutic regimens in blocking trophic inputs. This principle is exemplified in the relatively common and still incurable chronic lymphocytic leukemia (CLL), a disease of clonal CD5+ B cells requiring ongoing signaling from membrane receptors and cells within the tumor microenvironment. While considerable information has been gleaned about the bi-directional dialogue between CLL B cells and autologous T cells, little information is available about individual T-cell subsets, particularly Th17 cells, a unique subset of T helper cells. The scientific premise of this proposal comes from our findings that in CLL: [1] higher levels of Th17-related cytokines and numbers of circulating Th17 cells associate with better clinical outcomes; [2] leukemic B cells promote Th17 generation from autologous CD4 T cells in vitro; [3] expression of miR155, which promotes Th17 cell differentiation, is significantly higher in Th17 cells from CLL patients than in healthy subjects; [4] Th17 cells modulate CLL B-cell survival and growth in vitro and in vivo; and [5] treatment of nave CLL T cells from CLL patients with the PI3K? inhibitor idelalisib, significantly enhances Th17-cell generation. These findings underlie our central hypothesis that CLL B cells promote the generation of Th17 cells, which exert anti-tumor effects within the leukemic compartment. We expect that enhancing idelalisib's ability to positively affect Th17 generation and function will significantly improve its clinical value. Our long-range goal is to define this cellular bi-directional communication more clearly at the molecular level, so as to manipulate these interactions to therapeutic advantage. To advance our hypotheses and goal, we propose studies to: elucidate cellular and molecular mechanism(s) whereby leukemic B cells regulate Th17 cell generation in CLL, focusing on the STAT3/miR155 pathway (Aim 1); determine the influence of Th17 cells on leukemic B-cell survival, growth and maturation in vitro and in vivo (Aim 2) and investigate the effects of idelalisib on Th17-cell generation and function in CLL (Aim 3). The proposed work is innovative as it is the first to explore underlying mechanisms by which leukemic B cells regulate the generation and function of Th17 cells and the impact this regulation has on clinical outcome; it is also the first study of genome-wide miR expression in T cells from CLL patients. Also, these innovative studies will have considerable impact on CLL, since we will identify mechanisms generating Th17s in CLL and the impact this T-cell subset has on leukemic B cell growth, proliferation and maturation. Finally, we will determine if lower Th17-cell numbers in CLL patients with poor outcomes results from inherent differences in the CLL T or B cells. This will serve to better inform future studies on how to enhance Th17 responses in CLL as a therapeutic modality achieved by targeted drug therapy or adoptive immunotherapy.
B-cell chronic lymphocytic leukemia (CLL), the most common adult leukemia in the US, remains incurable and therefore there is an urgent need to develop new effective therapies based on a more precise understanding of disease pathophysiology. The objective of this proposal is to build upon our recent discovery of a previously unrecognized role for the Th17/IL-17 axis in improving the clinical course of CLL patients. Using a combination of molecular, cellular, and experimental model approaches, we will identify the pathways that induce and are mediated by the Th17/IL-17 axis in patients with CLL and that might be manipulated by the drug idelalisib to improve the outcome of patients with this still fatal disease.
