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Published on: December 14, 2019
SMAC mimetics induce human macrophages to phagocytose live cancer cells
Samantha Y Liu1, Max P M Hulsman1, Philipp Leyendecker1
1Dana-Farber Cancer Institute, Department of Cancer Immunology and Virology, Boston, Massachusetts, US.
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 a 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 IFNg. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNFa production.
Insights
SMAC mimetics reprogram macrophages to engulf live cancer cells. This class effect, enhanced by interferon-gamma in human cells, shows promise for cancer therapy by promoting phagocytosis.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Macrophages are crucial for cellular homeostasis through phagocytosis.
- Pharmacologic reprogramming can induce macrophages to phagocytose live cells, including cancer cells.
Purpose of the Study:
- To investigate the efficacy of various SMAC mimetic compounds in inducing live cancer cell phagocytosis by human macrophages.
- To compare the mechanisms of macrophage reprogramming in human versus mouse models.
Main Methods:
- Treatment of primary human macrophages with monovalent and bivalent SMAC mimetics.
- Co-administration with cytokines like lymphotoxin and interferon-gamma (IFN-γ).
- Transcriptional and proteomic profiling of phagocytic macrophages.
Main Results:
- SMAC mimetics broadly induce live cancer cell phagocytosis, a class effect.
- Primary human macrophages robustly phagocytosed live pancreatic and breast cancer cells.
- IFN-γ synergized with SMAC mimetics to enhance phagocytosis in human macrophages, unlike lymphotoxin in mouse models.
- Autocrine TNF-α production was identified as a key component of the phagocytic feedback loop.
Conclusions:
- SMAC mimetics represent a promising class of agents for reprogramming macrophages to target live cancer cells.
- Interferon-gamma is a key cytokine for enhancing SMAC mimetic-induced phagocytosis in human macrophages.
- Understanding the autocrine TNF-α loop provides insights into macrophage-mediated cancer cell clearance.
