Phagocytic Function of Macrophages Is Impaired By Chronic Lymphocytic Leukemia and high–grade Lymphoma Progression and Can be Highly Effectively Restored for Chemo-Immunotherapy

Macrophage polarity has recently been shown to play a pivotal role in progression and prognosis of human malignancies. In CLL the high dependence of the malignant cell to the tumor microenvironment has revealed macrophages as major mediators of leukemia cell survival. In contrast, macrophage activation also offers novel therapeutic strategies for leukemia cell targeting. Here we analyze the reciprocal relationship of leukemia cells and macrophages and the specific functional impact of phagocytosis in leukemia progression and therapy.

We employed the humanized hMB-Lymphoma and the Eµ-TCL1 CLL mouse model. Thioglycollate-induced macrophages, bone marrow derived murine macrophages and human monocyte derived macrophages were used for in vitroevaluation of phagocytosis either by bead based approaches or by ADCC.

Applying gene-expression profiling of macrophages in Eµ-TCL1 mice we could identify profound transcriptional alterations indicating a re-programming during leukemogenesis. Functional genomic analysis particularly revealed impaired phagocytic function induced during leukemia onset. In vivo and ex vivo phagocytosis assays of primary macrophages showed a significant reduced phagocytic activity during CLL progression. Human macrophages in co-culture with CLL cells in vitro compared to healthy B-cells similarly showed defects in phagocytosis. In the humanized leukemia model we similarly observed impaired phagocytosis resulting in resistance towards therapeutic antibody/macrophage mediated therapy. Resistance was actively induced by increasing leukemia cell infiltration in the bone marrow. Impaired macrophage function could be identified being mediated by secretory crosstalk such as release of PGE2 by leukemia cells and Cholecalciferol. We could restore phagocytic function by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, an acute secretory activating phenotype (ASAP), releasing cytokines from leukemia cells induces macrophage infiltration and phagocytic activity in the bone marrow. Thus, malignant cells can be effectively targeted by modulation of macrophage polarization and function.

In conclusion, we have identified decreased phagocytic activity of macrophages as key functional aspect in leukemia and lymphoma associated macrophages. Inversely, enhancing phagocytosis rendered essential for the re-sensitization of refractory niches treatment towards monoclonal antibodies defined by macrophage polarity. Overall macrophage function represents a key therapeutic target in CLL and other B-cell malignancies.