Cell Metabolism: Jun Yan's group reveals the detailed mechanism of macrophages promoting tumor metastasis

Tumor metastasis is the main cause of cancer death
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Previous studies have shown that innate immune cells, especially macrophages, play a very important role in tumor metastasis

However, in the microenvironment before tumor metastasis, the mechanism of how macrophages acquire immunosuppressive function to promote tumor metastasis has not yet been elucidated
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On September 23, 2021, the research group of Professor Jun Yan from the Cancer Center of the University of Louisville published a research paper on Cell Metabolism entitled: Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming
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The study found that exosomes (TDEs) secreted by primary tumor cells can induce tissues in the microenvironment before tumor metastasis to host macrophages to up-regulate the immunosuppressive molecule PD-L1 and secrete large amounts of lactic acid, thereby establishing an immunosuppressive microenvironment to promote tumors Transfer
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First, they proved that mouse lung cancer cell exosomes can promote lung metastasis of primary tumors
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Lung tissue biopsy revealed a large number of PD-L1 positive macrophages

The differentiation and function acquisition of macrophages are closely related to cell metabolism
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The traditional view is that macrophages with anti-tumor effects usually use glycolytic pathways to capture energy, while macrophages that promote tumor cell growth mainly use oxidative phosphorylation pathways as energy sources

This study shows that macrophages stimulated by tumor cell exosomes mainly use the glycolytic pathway to produce lactic acid, and the production of nitric oxide further inhibits the mitochondrial electron transport chain (ECT) oxidative phosphorylation pathway to produce more lactic acid
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Further studies have shown that lactic acid can directly activate the NF-kB signaling pathway to up-regulate the expression of PD-L1

The last part of the article is to use human tumor cell exosomes to also prove that it can stimulate monocytes to up-regulate PD-L1 and secrete lactic acid
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In order to verify the situation in humans, the authors selected the lymph nodes of non-metastatic non-small cell lung cancer (NSCLC) patients to simulate the pre-metastasis microenvironment, and used lymph nodes from lung transplant donors as normal controls

This study not only clarified the mechanism of the transformation of macrophages into immunosuppressive cells in the microenvironment before metastasis, but also provided clues on how to detect tumor metastasis early in the clinic
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This research is the result of a multi-center collaboration at the University of Louisville, and is also supported by the research group of Professor Huang Jian from Zhejiang Second Hospital of Zhejiang University
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The first author is PhD student Samantha Morrissey, the corresponding author is the titled professor of the University of Louisville, and Professor Yan Jun, the director of the Cancer Center's Immunotherapy Center.

Original source:

Original source:

Samantha M.

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