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Published on: December 14, 2019
SMAC mimetics induce human macrophages to phagocytose live cancer cells
Abstract:
Macrophages engulf apoptotic bodies and cellular debris as part of homeostasis, but they can also phagocytose live cells such as aged red blood cells. Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models. Here we extend these findings to encompass a wide range of monovalent and bivalent SMAC mimetic compounds, demonstrating that live cell phagocytosis is a class effect of these agents. We demonstrate robust phagocytosis of live pancreatic and breast cancer cells by primary human macrophages across a range of healthy donors. Unlike mouse macrophages where combination of SMAC mimetics with lymphotoxin enhanced phagocytosis, human macrophages were more efficiently polarized to phagocytose live cells by the combination of SMAC mimetics and IFNψ. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNFα production.
Insights
SMAC mimetics reprogram macrophages to phagocytose live cancer cells. Human macrophages efficiently clear pancreatic and breast cancer cells when treated with SMAC mimetics and interferon-gamma (IFNγ).
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Macrophages are crucial for cellular homeostasis, clearing apoptotic cells and debris.
- Pharmacologic reprogramming can enhance macrophage phagocytosis of live cells, including cancer cells.
Purpose of the Study:
- To investigate the efficacy of SMAC mimetic compounds in inducing live cancer cell phagocytosis by human macrophages.
- To compare the effects of different SMAC mimetics and cytokines on macrophage phagocytic activity.
Main Methods:
- Treatment of primary human macrophages with various SMAC mimetics.
- Co-treatment with T cell-derived cytokines (lymphotoxin or IFNγ).
- Assessment of phagocytosis of live pancreatic and breast cancer cells.
- Transcriptional and proteomic profiling of phagocytic macrophages.
Main Results:
- SMAC mimetics, as a class, induce macrophages to phagocytose live cancer cells.
- Primary human macrophages robustly phagocytosed live pancreatic and breast cancer cells.
- Interferon-gamma (IFNγ) was more effective than lymphotoxin in enhancing SMAC mimetic-induced phagocytosis in human macrophages.
- Transcriptional and proteomic analyses revealed an autocrine TNFα feedback loop in phagocytic macrophages.
Conclusions:
- SMAC mimetics represent a promising class of agents for reprogramming macrophages to target live cancer cells.
- The combination of SMAC mimetics and IFNγ is a potent strategy for enhancing macrophage-mediated cancer cell clearance in humans.
- Understanding the molecular mechanisms, such as the TNFα feedback loop, can inform the development of novel immunotherapies.
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