Background: Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western world. Targeted therapies have made CLL manageable for many patients, but the ongoing threat of disease relapse or transformation beckons a deeper understanding of CLL pathogenesis, and thus, its durable eradication. This study identifies bile acids (BAs) as elevated in the peripheral blood of CLL patients and a murine model of CLL, in comparison to healthy controls. Elevated BA concentrations have been associated with intestinal malignancies and immunomodulation; however, their role in CLL is relatively unknown. Methods: Metabolomic analysis was performed on murine and human plasma. Flow cytometry analysis of CLL patient B-cells and healthy donor T-cells were utilized to evaluate the immunomodulatory impact of differentially abundant BAs. Results: Herein, BAs were found to be differentially abundant in CLL. Elevated BAs demonstrated minimal impact on CLL cell proliferation or CLL-associated T-cell function. Conclusions: Future studies are needed to determine the mechanistic influence of BAs on CLL pathogenesis.

Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL.