Th1-polarizing cytokine IL-12 exhibits potent anti-tumor activity in multiple cancer models; however, therapeutic use of this cytokine is limited due to severe IFN-ã-mediated toxicity. To reduce the amount of IL-12 needed to elicit a therapeutic response, and thereby decrease associated toxicity, it is necessary to characterize novel cytokines to use in conjunction with IL-12. Newly described IL-12 family member IL-23 shares the IL-12 p40 subunit and promotes Th1 immunity by inducing IFN-ã expression and specifically stimulating proliferation of memory CD4+ T-cells. I have demonstrated that injection of an adenovirus expressing IL-23 (Ad.IL-23) into the tumor microenvironment results in significantly enhanced survival and tumor rejection in 40 percent of animals, with concomitant induction of protective anti-tumor immunity. Furthermore, the anti-tumor activity of IL-23 is dependent on IL-12, IFN-ã and CD4+ and CD8+ T-cells, indicating generation of a Th1 response. Delivery of adenovirus expressing IL-12 (Ad.IL-12) into the tumor microenvironment also results in enhanced survival and tumor rejection in up to 90 percent of animals. In contrast to Ad.IL-23, Ad.IL-12 anti-tumor activity requires only IFN-ã and induces protective immunity only 50 percent of the time, suggesting activation primarily of innate immunity. Due to the similar, yet divergent, effector mechanisms used in Ad.IL-12 and Ad.IL-23 anti-tumor effects, I hypothesized that use of these two viruses together would result in synergistic enhancement of tumor eradication. Surprisingly, Ad.IL-12 and Ad.IL-23 do not synergistically enhance anti-tumor effects over use of either cytokine alone, possibly due to IL-23 p19 sequestration of p40. To circumvent this possibility, adenovirus expressing single chain IL-23 (Ad.scIL-23) was constructed and characterized. Ad.scIL-23 expresses greater levels of cytokine than Ad.IL-23 and treatment of tumor bearing mice results in tumor rejection in 90 percent of animals. However, Ad.scIL-23 does not synergize with Ad.IL-12. Overall, I have shown that IL-23 does possess therapeutic anti-tumor effects, but does not synergize with IL-12 to enhance tumor eradication. Future studies could include characterizing CD4+ T-cell infiltrate of tumors treated with both Ad.IL-12 and Ad.IL-23 to elucidate the mechanism behind the lack of synergy between these two cytokines.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05202010-125900 |
| Date | 25 May 2010 |
| Creators | Reay, Ja'Nean Christine |
| Contributors | Paul Robbins, PhD, Hideho Okada, MD, PhD, Walter Storkus, Ph.D., Andrea Gambotto, MD, Jay Kolls, MD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-05202010-125900/ |
| Rights | unrestricted, 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 Pittsburgh 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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