University of SaskatchewanHARVEST
  • Login
  • Submit Your Work
  • About
    • About HARVEST
    • Guidelines
    • Browse
      • All of HARVEST
      • Communities & Collections
      • By Issue Date
      • Authors
      • Titles
      • Subjects
      • This Collection
      • By Issue Date
      • Authors
      • Titles
      • Subjects
    • My Account
      • Login
      JavaScript is disabled for your browser. Some features of this site may not work without it.
      View Item 
      • HARVEST
      • Electronic Theses and Dissertations
      • Graduate Theses and Dissertations
      • View Item
      • HARVEST
      • Electronic Theses and Dissertations
      • Graduate Theses and Dissertations
      • View Item

      IL-6-engineered DC stimulate efficient antitumor immunity via enhanced and prolonged T cell cytotoxicity and survival

      Thumbnail
      View/Open
      bei_Thesis.pdf (931.2Kb)
      Date
      2009
      Author
      Zhang, Bei
      Type
      Thesis
      Degree Level
      Masters
      Metadata
      Show full item record
      Abstract
      Dendritic cells (DCs) modified by some immunomodulatory genes can stimulate a strong antitumor immunity and improve the treatment of tumor cells on the condition that the sources of tumor-associated antigens (TAAs) are available. IL-6, a pleotropic cytokine, has been found to inhibit CD4+25+ regulatory T (Treg)-cell-mediated immune suppression and decrease activation-induced cell death (AICD) without interfering the process of T-cell activation. To enhance DC-based cancer vaccine, we engineered DCs to express transgene IL-6. We constructed a fiber-modified recombinant adenovirus vector AdVIL-6 expressing IL-6, infected DCs with AdVIL-6, and then investigated the efficacy of antitumor immunity induced by vaccination with DCs engineered to express IL-6 transgene. We demonstrated that DCs infected with the recombinant adenovirus AdVIL-6 induced DC maturation by up-regulation of the expression of MHC class ‡U (Iab), CD40, CD54 and CD80 expression. We also demonstrated that vaccination of OVA-pulsed AdVIL-6-infected DCs (DCOVA/AdVIL-6) was able to stimulate a stronger OVA-specific effector CD8+ cytotoxic T lymphocyte (CTL) response than vaccination with the control virus AdVpLpA-infected DCs (DCOVA/AdVpLpA). More importantly, vaccination of mice with DCOVA/AdVpLpA could protect 100% mice from intravenous (i.v.) challenge of a low dose (0.5 ~105 cells per mouse, 8/8 mice protected) of OVA-expressing BL6-10OVA tumor cells, but only 63% mice from i.v. challenge of a high dose (1 ~105 cells per mouse, 5/8 mice protected) of BL6-10OVA tumor cells. However, vaccination of DCOVA/AdVIL-6 induced an augmented antitumor immunity in vivo by complete protection of mice (8/8) from challenge of both low and high doses of BL6-10OVA tumor cells. To study the immune mechanism underlying the result of IL-6 engineered-DC vaccine, we generated the DCOVA/AdVIL-6-activated OTI CD8+ T cells and DCOVA/AdVpLpA-activated OTI CD8+ T cells. We demonstrated that DCOVA/AdVIL-6-activated CD8+ T cells displayed a higher level of CD62L, FasL and perforin than DCOVA/AdVpLpA-activated CD8+ T cells. DCOVA/AdVIL-6-activated CD8+ T cells had a prolonged T cell survival after they were transferred into C57BL/6 mice. Furthermore, the results of the animal study showed that 100% of mice bearing OVA-expressing EG7 tumors (8mm in diameter, 8 mice per group) were tumor-free after they were i.v. treated with DCOVA/AdVIL-6-activated CD8+ T cells (2 ~106 cells per mouse). However, the control DCOVA/AdVpLpA-activated CD8+ T cells failed in eradication of EG7 tumors in all 8/8 mice. Taken together, Adenovirus-mediated IL-6 transgene engineered DC vaccine stimulates efficient CD8+ T cell responses and antitumor immunity via enhanced T cell cytotoxicity and prolonged T cell survival. DCs engineered to express IL-6 by adenovirus-mediated IL-6 gene transfer may offer a new strategy in production of DC cancer vaccines.
      Degree
      Master of Science (M.Sc.)
      Department
      Pathology
      Program
      Pathology
      Supervisor
      Xiang, Jim
      Committee
      Saxena, Anurag; Qureshi, Mabood; Krahn, John; Chibbar, Rajni; Xu, Qingyong
      Copyright Date
      2009
      URI
      http://hdl.handle.net/10388/etd-02262009-152419
      Subject
      antitumor
      T cells
      DC
      IL-6
      Collections
      • Graduate Theses and Dissertations
      University of Saskatchewan

      University Library

      © University of Saskatchewan
      Contact Us | Disclaimer | Privacy