A Novel Cancer Therapeutic Using Thrombospondin 1 in Dendritic Cells

作者：Weng Tzu Yang; Huang Shih Shien; Yen Meng Chi; Lin Chi Chen; Chen Yi Ling; Lin Chiu Mei; Chen Wei Ching; Wang Chih Yang; Chang Jang Yang; Lai Ming Derg^*

来源：Molecular Therapy, 2014, 22(2): 292-302.

DOI：10.1038/mt.2013.236

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.

• 出版日期2014-2