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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant
Samantha M Morrissey1, Fan Zhang2, Chuanlin Ding3
1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Abstract:
One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
Insights
Tumor exosomes reprogram macrophage metabolism, promoting an immunosuppressive phenotype crucial for metastasis. This highlights a link between exosomes, metabolism, and cancer spread.
Area of Science:
- Cancer Biology
- Immunology
- Metabolic Reprogramming
Background:
- Pre-metastatic niche formation requires immunosuppressive macrophages.
- The mechanisms driving macrophage polarization in this niche are poorly understood.
Purpose of the Study:
- To elucidate how tumor-derived exosomes (TDEs) induce an immunosuppressive phenotype in macrophages.
- To investigate the role of metabolic reprogramming in this process.
Main Methods:
- Investigated TDEs' effect on macrophage polarization and PD-L1 expression.
- Analyzed metabolic pathways, including glucose uptake and lactate production.
- Utilized NF-kB and TLR2 signaling pathway analysis.
- Examined patient lymph node samples from non-small-cell lung cancer patients.
Main Results:
- TDEs polarize macrophages to an immunosuppressive phenotype via NF-kB-dependent, glycolytic reprogramming.
- TDEs increase glucose uptake and NOS2 expression, leading to lactate production.
- Lactate enhances NF-kB signaling, further increasing PD-L1 expression.
- Macrophage PD-L1 correlates with GLUT-1 and YKT6 in patient samples.
Conclusions:
- TDEs drive macrophage immunosuppression through metabolic reprogramming, linking exosomes, metabolism, and metastasis.
- This mechanism is critical for establishing the pre-metastatic niche.
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