Journal
MOLECULAR THERAPY
Volume 22, Issue 2, Pages 292-302Publisher
CELL PRESS
DOI: 10.1038/mt.2013.236
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Funding
- National Science Council, Taiwan [NSC-102-2325-B-006-007]
- National Health Research Institute, Taiwan [NHRI-EX10019927B1]
- Department of Health, Executive Yuan, Taiwan [DOH101-TD-C-111-003]
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Induction of thrombospondin 1 (TSP-1) is generally assumed to suppress tumor growth through inhibiting angiogenesis; however, it is less clear how TSP-1 in dendritic cells (DCs) influences tumor progression. We investigated tumor growth and immune mechanism by downregulation of TSP-1 in dendritic cells. Administration of TSP-1 small hairpin RNA (shRNA) through the skin produced anticancer therapeutic effects. Tumorinfiltrating CD4(+) and CD8(+) T cells were increased after the administration of TSP-1 shRNA. The expression of interleukin-12 and interferon-7 in the lymph nodes was enhanced by injection of TSP-1 shRNA. Lymphocytes from the mice injected with TSP-1 shRNA selectively killed the tumor cells, and the cytotoxicity of lymphocytes was abolished by depletion of CD8(+) T cells. Injection of CD11c(+) TSP-1 knockout (TSP-1-KO) bone marrow derived DCs (BMDCs) delayed tumor growth in tumorbearing mice. Similarly, antitumor activity induced by TSP-1-K0 BMDCs was abrogated by depletion of CD8(+) T cells. In contrast, the administration of shRNAs targeting TSP-2, another TSP family member, did not extend the survival of tumor-bearing mice. Finally, TSP-1 shRNA functioned as an innmunotherapeutic adjuvant to augment the therapeutic efficacy of Neu DNA vaccination. Collectively, the downregulation of TSP-1 in DCs produces an effective antitumor response that is opposite to the protumor effects by silencing of TSP-1 within tumor cells.
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