title: IL-21-Expressing Mesenchymal Stem Cells Prevent Lethal B-Cell Lymphoma Through Efficient Delivery of IL-21, Which Redirects the Immune System to Target the Tumor.
abstract: Interleukin (IL)-21, a proinflammatory cytokine, has been developed as an immunotherapeutic approach due to its effects on various lymphocytes, including natural killer (NK) cells and T cells; however, the clinical success in cancer patients has been limited. Recently, mesenchymal stem cells (MSCs) have emerged as vehicles for cancer gene therapy due to their inherent migratory abilities toward tumors. In the present study, we hypothesized that MSCs, genetically modified to express high levels of IL-21 (IL-21/MSCs), can enhance antitumor responses through localized delivery of IL-21. For tumor induction, BALB/c mice were injected intravenously with syngeneic A20 B-cell lymphoma cells to develop a disseminated B-cell lymphoma model. Then, 6 days following tumor induction, the tumor-bearing mice were treated with IL-21/MSCs weekly, four times. Systemic infusion of A20 cells led to hind-leg paralysis as well as severe liver metastasis in the control group. The IL-21/MSC-treated group showed delayed tumor incidence as well as improved survival, whereas the MSC- and recombinant adenovirus-expressing IL-21 (rAD/IL-21)-treated groups did not show significant differences from the untreated mice. These therapeutic effects were associated with high levels of IL-21 delivered to the liver, which prevented the formation of tumor nodules. Furthermore, the infusion of IL-21/MSCs led to induction of effector T and NK cells, while potently inhibiting immune suppressor cells. Our findings demonstrate that IL-21-expressing MSCs have the therapeutic potential to induce potent antitumor effects against disseminated B-cell lymphoma through localized IL-21 delivery and induction of systemic antitumor immunity.
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease , Seoul, Korea.
authors.forename: Nayoun
authors.initials: N
authors.lastname: Kim
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease , Seoul, Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Nam
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease , Seoul, Korea.
authors.forename: Keon-Il
authors.initials: KI
authors.lastname: Im
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease , Seoul, Korea.
authors.forename: Jung-Yeon
authors.initials: JY
authors.lastname: Lim
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease , Seoul, Korea.
authors.forename: Eun-Sol
authors.initials: ES
authors.lastname: Lee
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|3 Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine , Seoul, Korea.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Jeon
authors.affiliation: 1 Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine , Seoul, Korea.|2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease , Seoul, Korea.|3 Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine , Seoul, Korea.
authors.forename: Seok-Goo
authors.initials: SG
authors.lastname: Cho
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000517:prevention & control / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21