Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells.
Dendritic cells (DC)-derived or tumor-derived exosomes are a population of nanometer sized membrane vesicles that can induce specific anti-tumor immunity. However, the immunogenic potential and efficiency of exosomes-based tumor vaccine are not satisfactory enough to achieve a curative effect in clinical trials. In this article we investigated whether IL-18 genetic modification of tumor cells can increase the efficacy of exosomes derived from IL-18 gene-modified tumor cells. We transfected carcinoembryonic antigen (CEA)-expressing tumor cells with a recombinant adenovirus encoding human IL-18 (AdhIL-18) and prepared the exosomes, Exo/IL-18, from IL-18 gene-modified tumor cells. We found that Exo/IL-18 naturally contain CEA and bioactive IL-18. Moreover, Exo-IL-18 are potent in chemoattracting DC and T cells, enhancing the proliferation and Th1 cytokine release of PBMC, and promoting the phenotypic and functional maturation of DC. Furthermore, Exo/IL-18-pulsed DC are quite potent to induce HLA-A*0201-restricted, CEA-specific CD8(+) CTL from the PBMC of HLA-A*0201 CEA(+) cancer patients in vitro. In almost all of these experiments, Exo/IL-18 show more potent functions than the conventionally prepared exosomes derived from parent tumor cells without IL-18 gene modification. Our findings suggest that Exo/IL-18 has more potent capability to induce specific anti-tumor immunity, and our strategy of IL-18 modification of exosomes is a feasible approach to develop exosomes-based tumor vaccines.
Dai
Shengming
S
Institute of Immunology, Zhejiang University, Hangzhou, 310031, People's Republic of China.
Zhou
Xiangyang
X
Wang
Baomei
B
Wang
Qingqing
Q
Fu
Yangxin
Y
Chen
Taoyong
T
Wan
Tao
T
Yu
Yizhi
Y
Cao
Xuetao
X
D000256:Adenoviridae / Q000235:genetics; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005240:Feasibility Studies; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000502:physiology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D016827:CD8 Antigens; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D015789:HLA-A2 Antigen; D020382:Interleukin-18