Activated local immunity by CC chemokine ligand 19-transduced embryonic endothelial progenitor cells suppresses metastasis of murine ovarian cancer.
Although tumor microenvironments play a key role in successful tumor immunotherapy, effective manipulation of local immunity is difficult because of the lack of an appropriate target system. It is well known that bone marrow-derived endothelial progenitor cells (EPCs) are actively recruited during tumor angiogenesis. Using this feature, we attempted to establish a novel therapeutic modality that targets tumor vessels of multiple metastases using embryonic endothelial progenitor cells (eEPCs) transduced with an immune-activating gene. The eEPCs were retrovirally transduced with the mouse CC chemokine ligand 19 (CCL19) gene, a lymphocyte-migrating chemokine. The mouse ovarian cancer cell line OV2944-HM-1 (HM-1) was inoculated subcutaneously into B6C3F1 mice, along with CCL19-tranduced eEPCs (eEPC-CCL19), resulting in immunologic activity and tumor-inhibitory effects. In this model, eEPC-CCL19 showed tumor repression accompanied by increased tumor-infiltrating CD8+ lymphocytes compared with the control group. In contrast, no tumor repression was observed when the same experiment was done in immunodeficient (SCID) mice, suggesting a crucial role of T-cell function in this system. Next, we established a lung metastasis model by injecting HM-1 cells or B16 melanoma cells via the tail vein. Subsequent intravenous injection of eEPC-CCL19 leads to a decrease in the number of lung metastasis and prolonged survival. Antitumor effects were also observed in a peritoneal dissemination model using HM-1. These results suggest that systemic delivery of an immune-activating signal using EPCs can alter the tumor immune microenvironment and lead to a therapeutic effect, which may provide a novel strategy for targeting multiple metastases of various malignancies.
Hamanishi
Junzo
J
Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Mandai
Masaki
M
Matsumura
Noriomi
N
Baba
Tsukasa
T
Yamaguchi
Ken
K
Fujii
Shingo
S
Konishi
Ikuo
I
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D054415:Chemokine CCL19 / Q000096:biosynthesis* / Q000235:genetics; D053595:Embryonic Stem Cells / Q000276:immunology / Q000637:transplantation*; D042783:Endothelial Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D012190:Retroviridae / Q000235:genetics; D033581:Stem Cell Transplantation; D013997:Time Factors; D014161:Transduction, Genetic; D047368:Tumor Burden
C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19