Therapy-resistant microenvironments represent a major barrier towards effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment-refractory B-cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemo-immunotherapeutic regimen represents a potent strategy for using conventional anti-cancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.
Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5 þ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5 þ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n ¼ 26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a halfmaximal dose (IC 50 ) of 2.35 lM. In healthy B cells a significantly higher mean IC 50 of 148.5 lM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; Po0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P ¼ 0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL.
Survival of chronic lymphocytic leukemia (CLL) cells is triggered by several stimuli, such as the B-cell receptor (BCR), CD40 ligand (CD40L), or interleukin-4 (IL-4).We identified that these stimuli regulate apoptosis resistance by modulating sphingolipid metabolism. Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of proapoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared with untreated controls. Antiapoptotic glucosylceramide levels were significantly increased after BCR cross-linking. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via UDPglucose ceramide glucosyltransferase (UGCG). Besides specific UGCG inhibitors, our data demonstrate that IgMmediated UGCG expression was inhibited by the novel and highly effective PI3K␦ and BTK inhibitors CAL-101 and PCI-32765, which reverted IgM-induced resistance toward apoptosis of CLL cells. Sphingolipids were recently shown to be crucial for mediation of apoptosis via mitochondria. Our data reveal ABT-737, a mitochondria-targeting drug, as interesting candidate partner for PI3K␦ and BTK inhibition, resulting in synergistic apoptosis, even under protection by the BCR. In summary, we identified the mode of action of novel kinase inhibitors CAL-101 and PCI-32765 by controlling the UGCGmediated ceramide/glucosylceramide equilibrium as a downstream molecular switch of BCR signaling, also providing novel targeted treatment options beyond current chemotherapy-based regimens. (Blood. 2012;120(19):3978-3985) IntroductionDespite recent advances in the treatment of chronic lymphocytic leukemia (CLL) by use of modern chemoimmunotherapies, 1,2 the disease remains incurable for most patients with the exception of those who have the option of an allogeneic transplantation. 3 Moreover, most chemotherapeutic regimens require a certain physical fitness of the patient. Because CLL is a disease of the elderly, there is a need for novel therapeutic concepts, which are able to disrupt resistance to cytostatic drugs. Chemoresistance is thought to be partially the result of malignant cell clones that find a niche within the microenvironment. Resistance might be mediated at least by 3 major stimuli: (1) by engagement of the B-cell receptor (BCR), (2) by CD40 ligand (CD40L)-CD40 interaction, and (3) by stimulation via interleukin-4 (IL-4). 4 Those signals lead via downstream pathways to reduced susceptibility of CLL cells toward chemotherapy within the microenvironment. To some extent, these stimuli share common pathways to mediate survival. 5 As a consequence, the balance between proapoptotic and antiapoptotic signals is disrupted toward pro-survival signals. BCR signaling has been identified as the central and determining factor in CLL. Therefore, novel compounds, which target this pathway, have been developed: CAL-101 as PI3K␦ inhibitor and PCI-32765 as inhibitor of Bruton tyrosine kinase (BTK).Recent data from first trials using CAL-101 and PCI-32765 ind...
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