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. Tumor-infiltrating CD4 + and CD8 + T cells were increased after the administration of TSP-1 shRNA. The expression of interleukin-12 and interferon-γ 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 tumor-bearing mice. Similarly, antitumor activity induced by TSP-1-KO 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 immunotherapeutic 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.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Drug Discovery
Weng, T. Y., Huang, S. S., Yen, M. C., Lin, C. C., Chen, Y. L., Lin, C. M., Chen, W. C., Wang, C. Y., Chang, J. Y., & Lai, M. D. (2014). A novel cancer therapeutic using thrombospondin 1 in dendritic cells. Molecular Therapy, 22(2), 292-302. https://doi.org/10.1038/mt.2013.236