To improve immunotherapy for hepatocellular carcinoma (HCC), Chen et al. fused the dendritic cell (DC) chemokine XCL1 to glypican-3 (GPC3) that is specific for malignant hepatocytes. Cells expressing XCL1-GPC3 chemoattracted XCR1+ mouse CD8α+ and human CD141+ DCs in vitro and increased IL-12 levels. Immunization with mXcl1-GPC3 plasmid in a liver model before or after tumors had formed significantly inhibited tumor growth and increased GPC3-specific CD8+ T cell infiltration as well as IFNγ and GRZB levels; this effect was augmented by anti-PD-1. Similar results were obtained in HCC-PDX models using autologous DC-stimulated T cells.
Contributed by Katherine Turner
Cancer vaccines can amplify existing antitumor responses or prime naive T cells to elicit effector T-cell functions in patients through immunization. Antigen-specific CD8+ T cells are crucial for the rejection of established tumors. We constructed XCL1-GPC3 fusion molecules as a liver cancer vaccine by linking the XCL1 chemokine to glypican-3 (GPC3), which is overexpressed in hepatocellular carcinoma (HCC). Cells expressing XCL1-GPC3 chemoattracted murine XCR1+CD8alpha+DCs and human XCR1+CD141+DCs in vitro and promoted their IL-12 production. After subcutaneous mXcl1-GPC3 plasmid injection, mXCL1-GPC3 was mainly detected in CD8alpha+DCs of mouse draining lymph nodes. XCL1-GPC3-targeted DCs enhanced antigen-specific CD8+ T cell-proliferation and induced the de novo generation of GPC3-specific CD8+ T cells, which abolished GPC3-expressing tumor cells in mouse and human systems. We immunized a murine autochthonous liver cancer model, with a hepatitis B background, with the mXcl1-GPC3 plasmid starting six weeks, when malignant hepatocyte clusters formed, or 14 weeks, when liver tumor nodules developed, after diethylnitrosamine administration. mXcl1-GPC3 immunized mice displayed significantly inhibited tumor formation and growth compared to GPC3-immunized mice. After mXcl1-GPC3 immunization, mouse livers showed elevated production of IFNgamma, granzyme B, IL-18, CCL5, CXCL19, Xcl1, and increased infiltration of GPC3-specific CD8+ T cells, activated NK cells and NKT cells. The antitumor effects of these immune cells were further enhanced by the administration of anti-PD1. Anti-HCC effects induced by hXCL1-GPC3 were confirmed in HCC-PDX model from three patients. Thus, XCL1-GPC3 might be a promising cancer vaccine to compensate for the deficiency of the checkpoint blockades in HCC immunotherapy.
Author Info: (1) State Key Lab of Molecular Oncology & Immunology Department, Cancer Institute, Chinese Academy of Medical Sciences. (2) State Key Lab of Molecular Oncology, Cancer Institute, C
Author Info: (1) State Key Lab of Molecular Oncology & Immunology Department, Cancer Institute, Chinese Academy of Medical Sciences. (2) State Key Lab of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences. (3) Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. (4) Department of Immunology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences. (5) Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medicine. (6) Department of Immunology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences. (7) Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. (8) Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. (9) immunology, Chinese Academy of Medical Sciences. (10) Department of Immunology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences. (11) Department of abdominal surgical oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. (12) State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. (13) Dept. of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. (14) Dept of Immunology, Shandong University School of Basic Medical Science. (15) State Key Lab of Molecular Oncology & Immunology Department, Cancer Institute, Chinese Academy of Medical Sciences quchf@cicams.ac.cn.
