Macrophage Phagocytosis in Cancer Immunotherapy
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the most prevalent lymphoid malignancy in many regions of the world including the United States (~140,000 patients). The addition of therapeutic unconjugated CD20 monoclonal antibodies (mAb) to chemotherapies that target B cell proliferation has significantly improved CLL patient outcomes and survival. Despite these advances, however, current therapies do not eliminate all CLL cells capable of division and are thus not curative, and most CLL patients will die from progressive disease or its complications. The therapeutic efficacy of CD20 mAb is dependent on immune cell-mediated killing of malignant cells, and current evidence indicates that antibody-dependent cell phagocytosis (ADCP) by tissue macrophages is one of the most important cellular mechanisms of action for therapeutic CD20 monoclonal antibodies (mAb). However, the mechanisms by which mAbs mediate cell clearance or the underlying basis for resistance to these therapies are poorly understood.
Microscopy image of mouse bone marrow macrophages engulfing mAb-ligated lymphocytes (labeled with a purple fluorescent tracer dye).
In collaboration with the laboratory of Clive S. Zent, M.D. in the Wilmot Cancer Institute, we have several ongoing projects to address these questions: 1) Define the structural features of mAbs that control their ability to effectively induce macrophage ADCP, 2) Define the molecular regulation and immunoregulatory consequences of macrophage “exhaustion” that occurs upon mAb-mediated ADCP of B cells. Our long-term goal is apply these new findings toward the development of more effective mAb therapies for CLL and other types of cancer.
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Zent CS and Elliott MR. Maxed out macs: physiologic cell clearance as a function of macrophage phagocytic capacity. FEBS J. 284:1021 (2017), PMID: 27863012; PMCID: PMC5378628.