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Gemcitabine-loaded synthetic high-density lipoprotein preferentially eradicates hepatic monocyte-derived macrophages in mouse liver with colorectal cancer metastases

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Abstract

Liver metastasis of colorectal cancer (CRC) is the critical cause of CRC-related death due to its unique immunosuppressive microenvironment. In this study we generated a gemcitabine-loaded synthetic high-density lipoprotein (G-sHDL) to reverse immunosuppression in livers with CRC metastases. After intravenous injection, sHDL targeted hepatic monocyte-derived alternatively activated macrophages (Mono-M2) in the livers of mice bearing both subcutaneous tumors and liver metastases. The G-sHDL preferentially eradicated Mono-M2 in the livers with CRC metastases, which consequently prevented Mono-M2-mediated killing of tumor antigen-specific CD8+ T cells in the livers and thus improved the densities of tumor antigen-specific CD8+ T cells in the blood, tumor-draining lymph nodes and subcutaneous tumors of the treated mice. While reversing the immunosuppressive microenvironment, G-sHDL also induced immunogenic cell death of cancer cells, promoted maturation of dendritic cells, and increased tumor infiltration and activity of CD8+ T cells. Collectively, G-sHDL inhibited the growth of both subcutaneous tumors and liver metastases, and prolonged the survival of animals, which could be further improved when used in conjunction with anti-PD-L1 antibody. This platform can be a generalizable platform to modulate immune microenvironment of diseased livers.

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Fig. 1: Schematic illustration of preparation and mechanism of G-sHDL.
Fig. 2: Liver metastases alter the hepatic immune microenvironment.
Fig. 3: Preferential uptake of sHDL by Mono-M2.
Fig. 4: G-sHDL reverses the immunosuppressive microenvironment in the livers and reduces the apoptosis of tumor antigen-specific CD8+ T cells.
Fig. 5: Antitumor immunity of the G-sHDL.
Fig. 6: Antitumor efficacy induced by sHDL.

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Acknowledgements

This work was financially supported by National Natural Science Foundation of China (32171374, 82270064, and 31870995) and Shandong Provincial Natural Science Foundation (ZR2019ZD25). The authors thank the staff of the Integrated Laser Microscopy System at the National Facility for Protein Science in Shanghai (NFPS) at Shanghai Advanced Research Institute, Chinese Academy of Sciences for sample preparation, data collection, and analysis. We thank scidraw.io for the mouse schematic.

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Authors and Affiliations

  1. China State Institute of Pharmaceutical Industry, Shanghai, 201203, China

    Feng-qin Xiong, Wen Zhang, Chao Zheng, Xiang Gong & Hao Wang

  2. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Feng-qin Xiong, Wen Zhang, Chao Zheng, Xiang Gong, Peng-cheng Zhang & Ya-ping Li

  3. Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China

    Yuan Zhang

  4. School of Biomedical Engineering, ShanghaiTech University, Shanghai, 201210, China

    Peng-cheng Zhang

  5. Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264000, China

    Ya-ping Li

  6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Yu Li & Ya-ping Li

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  1. Feng-qin Xiong
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Contributions

FQX and PCZ designed the research; FQX, WZ, CZ, YL, and XG performed the experiments; FQX, WZ, CZ, YL, XG, YZ, and PCZ analyzed the data; HW, PCZ, and YPL supervised the research; all the authors wrote and edited the manuscript.

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Correspondence to Hao Wang, Peng-cheng Zhang or Ya-ping Li.

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Xiong, Fq., Zhang, W., Zheng, C. et al. Gemcitabine-loaded synthetic high-density lipoprotein preferentially eradicates hepatic monocyte-derived macrophages in mouse liver with colorectal cancer metastases. Acta Pharmacol Sin 44, 2331–2341 (2023). https://doi.org/10.1038/s41401-023-01110-w

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