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

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 i...

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Veröffentlicht in:Acta pharmacologica Sinica 2023-11, Vol.44 (11), p.2331-2341
Hauptverfasser: Xiong, Feng-qin, Zhang, Wen, Zheng, Chao, Li, Yu, Gong, Xiang, Zhang, Yuan, Wang, Hao, Zhang, Peng-cheng, Li, Ya-ping
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Sprache:eng
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Zusammenfassung: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.
ISSN:1671-4083
1745-7254
1745-7254
DOI:10.1038/s41401-023-01110-w