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Lipid-related FABP5 activation of tumor-associated monocytes fosters immune privilege via PD-L1 expression on Treg cells in hepatocellular carcinoma

Abstract

Monocytes/macrophages, a plastic and heterogeneous cell population of the tumor microenvironment (TME), can constitute a major component of most solid tumors. Under the pressure of rapid proliferation of the tumor, monocytes/macrophages can be educated and foster immune tolerance via metabolic reprogramming. Our studies have shown that the activation of FABP5, a lipid-binding protein, decreases the rate of β-oxidation causing the accumulation of lipid droplets in monocytes. We found that hepatocellular carcinoma cells (HCC) increased IL-10 secretion by monocytes, which depended on the expression of FABP5 and suppressing of the PPARα pathway. Moreover, the elevated level of IL-10 promotes PD-L1 expression on Treg cells via the JNK-STAT3 pathway activation. We also observed that elevation of FABP5 in monocytes was negatively related to HCC patients’ overall survival time. Thus, FABP5 promotes monocyte/macrophage lipid accumulation, fosters immune tolerance formation, and might represent itself as a therapeutic target in both tumor-associated monocytes (TAMs) and cancer cells.

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Fig. 1: Monocytes occurred predominantly in the tumor stroma of HCC, and were associated with Treg cells density.
Fig. 2: Lipid metabolism reprogramming mediates tumor-induced immune privilege by monocytes.
Fig. 3: FABP5 in monocytes mediates lipid accumulation-induced PD-L1 expression on Treg cells.
Fig. 4: IL-10 is required for PD-L1 expression on Treg cells.
Fig. 5: FABP5 induces PD-L1 upregulation on Treg cells via JNK-STAT3 signaling pathway.
Fig. 6: The tumor-associated monocytes reshape the immune tolerance microenvironment in HCC.

Data availability

The mass spectrometry proteomics data have been deposited to the Proteome Xchange Consortium via the PRIDE [46] partner repository with the dataset identifier PXD030840.

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Acknowledgements

This work was supported by the fund from the National Natural Science Foundation of China (81972749), Science and Technology Program of Liaoning Province (2018225056, 2021JH2/10300020), and Innovative Teams Project in Key Areas of Dalian (2021RT01). We are also very grateful to Professor Kuang from Sun Yat-sen University, Guangzhou, PR China for his selfless technical guidance in this experiment and Professor Yu from the Dalian Blood Center, Associate Professor Chu from Dalian Institute of Chemical Physics, Chinese Academy of Sciences for their generous help in this research. In the meanwhile, we deeply appreciate the patients’ generous support for this research.

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JL and LW developed the main concept and designed the study. JL processed tissues, cultured cells, performed flow cytometry, western blotting and Elisa, collected the data, and wrote the paper, drew all the pictures and tables. BS did the part of proteomic analysis with LC-MS/MS, KG helped collected pathological specimens and did immunohistochemical staining, ZY and YZ did Q-PCR verification, MG, ZY, KJ, CD assisted with the literature collection part of the manuscript and take part in designing the study. ZG, MY, and JL provided guidance and the proofreading of the article. LW supervised the whole process and provided suggestions for the article writing.

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Correspondence to Jing Liu or Liming Wang.

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Liu, J., Sun, B., Guo, K. et al. Lipid-related FABP5 activation of tumor-associated monocytes fosters immune privilege via PD-L1 expression on Treg cells in hepatocellular carcinoma. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00510-0

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