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 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.

Automated summary

In this study, we developed gemcitabine-loaded synthetic high-density lipoprotein (G-sHDL) to reverse immunosuppression in colorectal cancer (CRC) liver metastases. The G-sHDL targeted and eliminated immunosuppressive macrophages in the liver, leading to improved densities of tumor-specific CD8(+) T cells in various tissues and enhanced anti-tumor immune responses. Moreover, G-sHDL induced cancer cell death, promoted dendritic cell maturation, and increased infiltration and activity of CD8(+) T cells in the tumor microenvironment. Overall, G-sHDL inhibited tumor growth and prolonged the survival of mice, especially when combined with anti-PD-L1 antibody. This platform has the potential to modulate immune microenvironment in diseased livers.