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.<p>
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.<p>
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.<p>
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.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-02262009-152419 |
| Date | 06 March 2009 |
| Creators | Zhang, Bei |
| Contributors | Xiang, Jim, Saxena, Anurag, Qureshi, Mabood, Krahn, John, Chibbar, Rajni, Xu, Qingyong |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-02262009-152419/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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