Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSFopen access
- Authors
- Choi, K-J; Zhang, S-N; Choi, I-K; Kim, J-S; Yun, C-O
- Issue Date
- Jul-2012
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- IL-12; GM-CSF; oncolytic adenovirus
- Citation
- GENE THERAPY, v.19, no.7, pp.711 - 723
- Indexed
- SCIE
SCOPUS
- Journal Title
- GENE THERAPY
- Volume
- 19
- Number
- 7
- Start Page
- 711
- End Page
- 723
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/27511
- DOI
- 10.1038/gt.2011.125
- ISSN
- 0969-7128
- Abstract
- Interleukin (IL)-12 and granulocyte-monocyte colony-stimulating factor (GM-CSF) have recently been used as immunotherapeutic agents in cancer gene therapy. IL-12 and GM-CSF have differential roles in the antitumor immune response, as IL-12 targets T, NK and natural killer T (NKT) cells and GM-CSF principally targets antigen-presenting cells (APCs). To strengthen the therapeutic efficacy of these two cytokines, we generated an oncolytic adenovirus (Ad), Ad-Delta B7/IL12/GMCSF, coexpressing IL-12 and GM-CSF. Using a murine B16-F10 syngeneic tumor model, we show that Ad-Delta B7/IL12/GMCSF promoted antitumor responses and increased survival compared with an oncolytic Ad expressing IL-12 or GM-CSF alone (Ad-Delta B7/IL12 or Ad-Delta B7/GMCSF, respectively). By measuring cytotoxic T lymphocyte activity and interferon-gamma production, we show that the enhanced therapeutic effect was mediated by the induction of immune cell cytotoxicity. In situ delivery of Ad-Delta B7/IL12/GMCSF resulted in massive infiltration of CD4(+) T cells, CD8(+) T cells, NK cells and CD86(+) APCs into the tissue surrounding the necrotic area of the tumor. Moreover, GM-CSF effectively promoted antitumor immune memory, which was significantly augmented by IL-12. Lastly, IL12-expressing oncolytic Ads prevented tumor-induced thymic atrophy and was associated with reduced apoptosis and increased proliferation in the thymus. Taken together, these data demonstrate that an oncolytic Ad coexpressing IL-12 and GM-CSF is a potential therapeutic tool for the treatment of cancer. Gene Therapy (2012) 19, 711-723; doi:10.1038/gt.2011.125; published online 13 October 2011
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